Bio

Bio


Dr. Dhabhar is Associate Professor of Psychiatry, and a member of the Cancer Institute, Immunology Institute, and Neuroscience Program at Stanford University. He specializes in studying the effects of stress on immunity and health. He was the first to discover mechanisms by which short-term stress physiology enhances the body's immune defenses to increase protection during a fight-or-flight response. He has proposed that fight-or-flight stress is generally “good” stress and represents one of Mother Nature's fundamental but under-appreciated survival systems. He is working on harnessing this system clinically to boost protective immune responses during surgery, vaccination, and cancer. Dr. Dhabhar also investigates mechanisms through which long-term or chronic stress increases chronic inflammation, accelerates immune cell aging, and has harmful effects on brain and body.

Working with colleagues at Stanford, UCSF, and UC Davis, Dr. Dhabhar has become keenly interested in developing practical and sustainable interventions to minimize “bad” stress and maximize “good” stress, in order to promote health and healing. He believes that activities/interventions (e.g. exercise, meditation, compassion, art, music) that reduce bad stress are likely to increase well-being and the protective effects of good stress, and to facilitate kind and caring behavior at the level of the individual and society.

Among Dr. Dhabhar's honors are the Council of Graduate Schools Distinguished Dissertation Award; the PsychoNeuroImmunology Society's Young Investigator Award for outstanding research; and the Richter Award for Excellence in Psychoneuroendocrinology. In addition to numerous highly-cited scientific publications, Dr. Dhabhar's work has been featured by many major media outlets including The New York Times, The Financial Times, USA Today, US News & World Report, Scientific American, ABC News, NBC News, and others. Dr. Dhabhar loves teaching and working with undergraduate and graduate students in the classroom and laboratory. He also enjoys interacting with diverse audiences of all ages, and has made numerous national and international presentations on different facets of his research.

Administrative Appointments


  • Director of Research, Stanford Center on Stress & Health (2006 - Present)
  • Adjunct Faculty, The Rockefeller University (1999 - Present)

Honors & Awards


  • Curt Richter Award, for Excellence in Psychoneuroendocrinology, International Society for Psychoneuroendocrinology (2011)
  • Young Investigator Award, PsychoNeuroImmunology Research Society (2000)
  • Distinguished Dissertation Award - Life Sciences, Council of Graduate Schools (1997)

Boards, Advisory Committees, Professional Organizations


  • Elected Member of Board of Directors, PsychoNeuroImmunology Research Society (2011 - Present)
  • Scientific Affairs Committee, PsychoNeuroImmunology Research Society (2013 - Present)

Professional Education


  • Ph.D., The Rockefeller University, Biomedical Sciences -- Neuroimmunology (1996)
  • AB, Dartmouth College, Biological Science (1990)
  • AB, Dartmouth College, Government (1990)

Community and International Work


  • Institute of Medicine Committee: Interactions Among Social, Behavioral and Genetic Factors In Health

    Partnering Organization(s)

    Institute of Medicine, The National Academies

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Institute for Laboratory Animal Research Committee: Humane Transport of Laboratory Animals

    Partnering Organization(s)

    Institute for Laboratory Animal Research, The National Academies

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Institute of Medicine Committee: Health Effects of Exposures Experienced During The Gulf War (I).

    Partnering Organization(s)

    Institute of Medicine, The National Academies

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Although stress has a bad reputation, the short-term, fight-or-flight stress response is nature's fundamental survival system. We are interested in elucidating biological mechanisms that mediate and differentiate the recently discovered immunoenhancing effects of short-term stress from the long-known immunosuppressive effects of chronic stress. We examine stress effects on leukocyte trafficking, innate/adaptive immunity, and cytokine gene/protein expression using models of skin immunity, vaccination, surgery, and cancer. By elucidating the mechanisms under investigation we hope to develop behavioral and/or pharmacologic interventions designed to harness a patient’s psycho-physiology to selectively enhance (during vaccination, surgery, infection, or cancer) or suppress (during inflammatory and autoimmune disease) an immune response depending on the clinical needs of the patient.

Clinical Trials


  • Sleep, Circadian Hormonal Dysregulation, and Breast Cancer Survival Not Recruiting

    Recent research provides evidence that disrupted circadian rhythms, including hormonal patterns and sleep, are associated with increased risk of breast cancer incidence and faster progression to mortality. We have observed that a loss of normal diurnal cortisol rhythm associated with more awakenings during the night predicts early mortality with metastatic breast cancer. Other recent studies have shown that nighttime shift work is associated with higher breast cancer incidence, and in a murine model disrupting circadian cortisol cycles produced a doubling of implanted tumor growth. There is also recent evidence that abnormal clock genes are associated with cancer. However, it is not clear whether sleep disruption per se affects breast cancer progression, or whether such an effect is mediated by hormonal and immune dysregulation of this prevalent and hormone-mediated cancer. We propose to study sleep disruption as a prognostic factor in the progression of metastatic breast cancer. We will also examine sleep patterns in association with disrupted circadian rhythms of cortisol, ACTH, and melatonin as well as measures of immune function known to be salient to breast cancer progression. These are natural killer cell cytoxicity and specific cytokine, IL-6. We plan to recruit 105 women 45 years through 75 years with metastatic or recurrent breast cancer and 20 age and SES-matched controls for a two-week at home sleep study with Actiwatch and two nights of in-home EEG monitoring, followed by 28 hours of continuous blood sampling and one night of EEG sleep monitoring in our lab at Stanford. This will provide a full examination of circadian hormones associated with sleep patterns. We will relate these assessments to the subsequent course of breast cancer progression. Results of this study will provide specific evidence regarding how improved sleep management may affect the course of breast cancer. Aim 1: To study 24-hr diurnal rhythms of HPA axis hormones and melatonin in women with metastatic or recurrent breast cancer. Hypothesis 1: Women with metastatic or recurrent breast cancer will have reduced amplitude and disrupted phase of 24-hr diurnal rhythms of cortisol, ACTH, and melatonin. Aim 2: To describe sleep disruption in women with metastatic breast cancer and examine psychosocial, endocrine, and immune factors that may be associated with sleep disruption. Hypothesis 2: Women with metastatic or recurrent breast cancer will have a higher incidence of both at home and laboratory-examined sleep disruption than control women without breast cancer. Hypothesis 3: Poorer sleep quality will be associated with more pain, more emotional suppression in response to stressors, less emotional support, greater depression and anxiety, and greater perceived and traumatic stress. Hypothesis 4: Poorer sleep quality and quantity of sleep and daytime sleepiness and fatigue will be associated with abnormal circadian neuroendocrine (i.e., cortisol, ACTH, and melatonin) and immune patterns (i.e., suppressed day and night time NK activity and loss of NK rhythms; increased day time IL-6 levels and /or loss of IL-6 rhythm). Aim 3: To study the relationship between sleep disruption and survival time among metastatic and recurrent breast cancer patients. Hypothesis 5: Poorer sleep quality and quantity of sleep will predict shorter survival. Hypothesis 6: Reduced diurnal amplitude and an abnormal phase of cortisol will predict shorter survival. Explanatory Aim 4: To investigate whether sleep disruption mediates the relation of psychosocial factors to health outcomes.

    Stanford is currently not accepting patients for this trial. For more information, please contact Bita Nouriani, (650) 723 - 8479.

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  • Acupuncture for Sleep Disruption in Cancer Survivors Not Recruiting

    The proposed study will recruit 60 women with breast cancer who finished undergoing treatment who complain of persistent insomnia problems that began with onset of their cancer diagnosis. The eligible women would be randomized and stratified by sleep problems to two arms: (Acupuncture Arm vs. Sham Acupuncture) with a goal of having 48 patients complete the study (we anticipate about 20% attrition rate). The study interventions will begin after patients completed their treatment. The placebo control for acupuncture will be a validated sham acupuncture control Assessments will be made with daily diaries and with weekly questionnaires. PSG data will be collected on the subsample of the population. Data will be gathered via pencil-and-paper measures before, during, immediately following, one month following the completion of treatment and six months after the conclusion of treatment. In addition, actigraphy data (objective sleep continuity data) will be acquired prior to and following treatment

    Stanford is currently not accepting patients for this trial. For more information, please contact David Spiegel, (650) 723 - 6421.

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Projects


  • Biomarkers & Mechanisms of Resilience Versus Susceptibility to Chronic Stress, Stanford University (May 15, 2013)

    As most people have personally experienced, stress is an intrinsic and increasingly dominant part of life for almost all human beings, and science has shown that chronic stress can exacerbate numerous disorders such as depression, heart disease, obesity, cancer, and autoimmune and infectious disease. It may be impossible to eliminate stress from our lives. However, a practical and useful way of grappling with stress is to minimize or eliminate the harmful effects of chronic (months to years) stress in order to maximize the recently appreciated adaptive/beneficial effects of short-term (minutes to hours) stress. Therefore, the proposed studies will identify biomarkers and mediators of resilience, susceptibility and recovery from chronic stress. The knowledge gained could be invaluable for the development of novel pharmacological and bio-behavioral treatments for stress and stress-related disorders, and for objectively monitoring the trajectory and efficacy of conventional and complementary/ alternative treatments for stress and diseases that are associated with stress.

    Location

    Stanford, CA, USA

  • Psychosocial Stress and Impaired Immune Cell Aging, UCSF and Stanford (September 1, 2010)

    Location

    CA

  • Immune Cell Aging in Major Depression, UCSF and Stanford (April 1, 2010)

    Location

    CA

  • Harnessing the Surgery Fight-or-Flight Response as a Predictor and Mediator of Post-Surgical Healing & Recovery, Stanford (March 1, 2013)

    Location

    CA

    Collaborators

  • Quantifiable Components of Spiritual Growth, UC Davis and Stanford (March 1, 2013)

    Location

    CA

Teaching

2013-14 Courses


Publications

Journal Articles


  • Poor sleep quality potentiates stress-induced cytokine reactivity in postmenopausal women with high visceral abdominal adiposity BRAIN BEHAVIOR AND IMMUNITY Prather, A. A., Puterman, E., Epel, E. S., Dhabhar, F. S. 2014; 35: 155-162
  • Psychological stress and immunoprotection versus immunopathology in the skin CLINICS IN DERMATOLOGY Dhabhar, F. S. 2013; 31 (1): 18-30

    Abstract

    Stress is thought to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate autoimmune/proinflammatory disorders (eg, psoriasis, atopic dermatitis) that should be ameliorated by immunosuppression. Here we review studies showing that although chronic stress (lasting for weeks/months/years) can suppress/dysregulate immune function, acute stress (lasting for minutes to hours) can have immunoenhancing effects. Short-term stress experienced at the time of immune activation enhances dendritic cell, neutrophil, macrophage, and lymphocyte trafficking, maturation, and function, and has been shown to augment innate and adaptive immunity; therefore, depending on the conditions of immune activation, and the nature of the activating antigen, short-term stress can enhance the acquisition and expression of immunoprotection or immunopathology. In contrast, chronic stress suppresses or dysregulates innate and adaptive immune responses by altering the Type 1-Type 2 cytokine balance, inducing low-grade chronic increases in proinflammatory factors, and suppressing numbers, trafficking, and function of immunoprotective cells. Chronic stress also increases susceptibility to skin cancer by suppressing Type 1 cytokines and protective T cells while increasing regulatory/suppressor T cell number/function. It is important to recognize that the adaptive function of a physiological stress response is to promote survival. Stress-related neurotransmitters, hormones, and factors act as biological alarm signals that prepare the immune and other physiological systems for potential challenges (eg, wounding or infection) perceived by the brain (eg, detection of an attacker); however, this may exacerbate immunopathology (eg, psoriasis, atopic dermatitis) if the enhanced immune response is directed against innocuous or self-antigens, or if the system is chronically activated as seen during long-term stress. In view of the ubiquitous nature of stress and its significant effects on immunoprotection and immunopathology, it is important to further elucidate the mechanisms mediating both the salubrious and the harmful effects of stress, and to meaningfully translate findings from bench to bedside.

    View details for DOI 10.1016/j.clindermatol.2011.11.003

    View details for Web of Science ID 000313316500004

    View details for PubMedID 23245970

  • Stress-induced redistribution of immune cells-From barracks to boulevards to battlefields: A tale of three hormones - Curt Richter Award Winner PSYCHONEUROENDOCRINOLOGY Dhabhar, F. S., Malarkey, W. B., Neri, E., McEwen, B. S. 2012; 37 (9): 1345-1368

    Abstract

    The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L-selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status.Male Sprague Dawley rats were stressed (short-term restraint, 2-120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations.Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L?/? neutrophils and CD62L? B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L?/? neutrophils and CD62L? monocytes, but decreased lymphocyte numbers with CD62L?/? CTL and CD62L? B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L? and CD62L? cells being equally affected. Thus, naïve (CD62L?) vs. memory (CD62L?) T cells, classical (CD62L?) vs. non-classical (CD62L?) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones.Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naïve or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function.

    View details for DOI 10.1016/j.psyneuen.2012.05.008

    View details for Web of Science ID 000307678800001

    View details for PubMedID 22727761

  • High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma PLOS ONE Dhabhar, F. S., Saul, A. N., Holmes, T. H., Daugherty, C., Neri, E., Tillie, J. M., Kusewitt, D., Oberyszyn, T. M. 2012; 7 (4)

    Abstract

    In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2-3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-? gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship.

    View details for DOI 10.1371/journal.pone.0033069

    View details for Web of Science ID 000305345200001

    View details for PubMedID 22558071

  • Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma BRAIN BEHAVIOR AND IMMUNITY Dhabhar, F. S., Saul, A. N., Daugherty, C., Holmes, T. H., Bouley, D. M., Oberyszyn, T. M. 2010; 24 (1): 127-137

    Abstract

    In contrast to chronic/long-term stress that suppresses/dysregulates immune function, an acute/short-term fight-or-flight stress response experienced during immune activation can enhance innate and adaptive immunity. Moderate ultraviolet-B (UV) exposure provides a non-invasive system for studying the naturalistic emergence, progression and regression of squamous cell carcinoma (SCC). Because SCC is an immunoresponsive cancer, we hypothesized that short-term stress experienced before UV exposure would enhance protective immunity and increase resistance to SCC. Control and short-term stress groups were treated identically except that the short-term stress group was restrained (2.5h) before each of nine UV-exposure sessions (minimum erythemal dose, 3-times/week) during weeks 4-6 of the 10-week UV exposure protocol. Tumors were measured weekly, and tissue collected at weeks 7, 20, and 32. Chemokine and cytokine gene expression was quantified by real-time PCR, and CD4+ and CD8+ T cells by flow cytometry and immunohistochemistry. Compared to controls, the short-term stress group showed greater cutaneous T-cell attracting chemokine (CTACK)/CCL27, RANTES, IL-12, and IFN-gamma gene expression at weeks 7, 20, and 32, higher skin infiltrating T cell numbers (weeks 7 and 20), lower tumor incidence (weeks 11-20) and fewer tumors (weeks 11-26). These results suggest that activation of short-term stress physiology increased chemokine expression and T cell trafficking and/or function during/following UV exposure, and enhanced Type 1 cytokine-driven cell-mediated immunity that is crucial for resistance to SCC. Therefore, the physiological fight-or-flight stress response and its adjuvant-like immuno-enhancing effects, may provide a novel and important mechanism for enhancing immune system mediated tumor-detection/elimination that merits further investigation.

    View details for DOI 10.1016/j.bbi.2009.09.004

    View details for Web of Science ID 000272676400017

    View details for PubMedID 19765644

  • Surgery stress induced immune cell redistribution profiles predict short- and long-term postsurgical recovery: A prospective study Journal of Bone and Joint Surgery Rosenberger, P.H., J. R. Ickovics, E. Epel, E. Nadler, P. Jokl, J. P. Fulkerson, J. M. Tillie, Dhabhar, F. S. 2009; 91: 2783-2794
  • Opinion - The influence of bio-behavioural factors on tumour biology: pathways and mechanisms NATURE REVIEWS CANCER Antoni, M. H., Lutgendorf, S. K., Cole, S. W., Dhabhar, F. S., Sephton, S. E., McDonald, P. G., Stefanek, M., Sood, A. K. 2006; 6 (3): 240-248

    Abstract

    Epidemiological studies indicate that stress, chronic depression and lack of social support might serve as risk factors for cancer development and progression. Recent cellular and molecular studies have identified biological processes that could potentially mediate such effects. This review integrates clinical, cellular and molecular studies to provide a mechanistic understanding of the interface between biological and behavioural influences in cancer, and identifies novel behavioural or pharmacological interventions that might help improve cancer outcomes.

    View details for DOI 10.1038/nrc1820

    View details for Web of Science ID 000235591900018

    View details for PubMedID 16498446

  • Chronic stress and susceptibility to skin cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE Saul, A. N., Oberyszyn, T. M., Daugherty, C., Kusewitt, D., Jones, S., Jewell, C., Malarkey, W. B., Lehman, A., Lemeshow, S., Dhabhar, F. S. 2005; 97 (23): 1760-1767

    Abstract

    Studies have shown that chronic stress or UV radiation independently suppress immunity. Given their increasing prevalence, it is important to understand whether and how chronic stress and UV radiation may act together to increase susceptibility to disease. Therefore, we investigated potential mediators of a stress-induced increase in emergence and progression of UV-induced squamous cell carcinoma.SKH1 mice susceptible to UV-induced tumors were unexposed (naïve, n = 4) or exposed (n = 16) to 2240 J/m2 of UVB radiation three times a week for 10 weeks. Half of the UVB-exposed mice were left nonstressed (i.e., they remained in their home cages) and the other half were chronically stressed (i.e., restrained during weeks 4-6). UV-induced tumors were measured weekly from week 11 through week 34, blood was collected at week 34, and tissues were collected at week 35. mRNA expression of interleukin (IL)-12p40, interferon (IFN)-gamma, IL-4, IL-10, CD3epsilon, and CCL27/CTACK, the skin T cell-homing chemokine, in dorsal skin was quantified using real-time polymerase chain reaction. CD4+, CD8+, and CD25+ leukocytes were counted using immunohistochemistry and flow cytometry. All statistical tests were two-sided.Stressed mice had a shorter median time to first tumor (15 versus 16.5 weeks, difference = 1.5 weeks, 95% confidence interval [CI] = -3.0 to 3.3 weeks; P = .03) and reached 50% incidence earlier than controls (15 weeks versus 21 weeks). Stressed mice also had lower IFN-gamma ( mean = 0.03 versus mean = 0.07, difference = 0.04, 95% CI = 0.004 to 0.073; P = .02), CCL27/CTACK (mean = 101 versus mean = 142, difference = 41, 95% CI = 8.1 to 74.4; P = .03), and CD3epsilon (mean = 0.18 versus mean = 0.36, difference = 0.18, 95% CI = 0.06 to 0.30; P = .007) gene expression and lower numbers of infiltrating CD4+ cells (mean = 9.40 versus mean = 13.7, difference = 4.3, 95% CI = 2.36 to 6.32; P = .008) than nonstressed mice. In addition, stressed mice had more regulatory/suppressor CD25+ cells infiltrating tumors and more CD4+ CD25+ cells in circulation (mean = 0.36 versus mean = 0.17, difference = 0.19, 95% CI = 0.005 to 0.38; P = .03) than nonstressed mice.Chronic stress increased susceptibility to UV-induced squamous cell carcinoma in this mouse model by suppressing type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell numbers.

    View details for DOI 10.1093/jnci/dji401

    View details for Web of Science ID 000233925000011

    View details for PubMedID 16333031

  • Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Dhabhar, F. S., Viswanathan, K. 2005; 289 (3): R738-R744

    Abstract

    It would be extremely beneficial if one could harness natural, endogenous, health-promoting defense mechanisms to fight disease and restore health. The psychophysiological stress response is the most underappreciated of nature's survival mechanisms. We show that acute stress experienced before primary immunization induces a long-lasting increase in immunity. Compared with controls, mice restrained for 2.5 h before primary immunization with keyhole limpet hemocyanin (KLH) show a significantly enhanced immune response when reexposed to KLH 9 mo later. This immunoenhancement is mediated by an increase in numbers of memory and effector helper T cells in sentinel lymph nodes at the time of primary immunization. Further analyses show that the early stress-induced increase in T cell memory may stimulate the robust increase in infiltrating lymphocyte and macrophage numbers observed months later at a novel site of antigen reexposure. Enhanced leukocyte infiltration may be driven by increased levels of the type 1 cytokines, IL-2 and IFN-gamma, and TNF-alpha, observed at the site of antigen reexposure in animals that had been stressed at the time of primary immunization. In contrast, no differences were observed in type 2 cytokines, IL-4 or IL-5. Given the importance of inducing long-lasting increases in immunologic memory during vaccination, we suggest that the neuroendocrine stress response is nature's adjuvant that could be psychologically and/or pharmacologically manipulated to safely increase vaccine efficacy. These studies introduce the novel concept that a psychophysiological stress response is nature's fundamental survival mechanism that could be therapeutically harnessed to augment immune function during vaccination, wound healing, or infection.

    View details for DOI 10.1152/ajpregu.00145.2005

    View details for Web of Science ID 000231243700014

    View details for PubMedID 15890793

  • Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity INTERNATIONAL IMMUNOLOGY Viswanathan, K., Daugherty, C., Dhabhar, F. S. 2005; 17 (8): 1059-1069

    Abstract

    Stress is thought to be immunosuppressive but paradoxically exacerbates inflammatory and autoimmune diseases. We initially showed that acute stress enhances skin immunity. Such immunoenhancement could promote immunoprotection in case of wounding, infection or vaccination but could also exacerbate immunopathological diseases. Here we identify the molecular and cellular mediators of the immunoenhancing effects of acute stress. Compared with non-stressed mice, acutely stressed animals showed significantly greater pinna swelling and leukocyte infiltration, and up-regulated macrophage chemoattractant protein-1, macrophage inflammatory protein-3alpha, IL-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha and IFN-gamma, but not IL-4 gene expression at the site of primary antigen exposure. Stressed animals also showed enhanced maturation and trafficking of dendritic cells (DCs) from skin to lymph nodes (LNs), higher numbers of activated macrophages in skin and LNs, increased T cell activation in LNs, and enhanced recruitment of surveillance T cells to skin. These findings show that important interactive components of innate (DCs and macrophages) and adaptive (surveillance T cells) immunity are mediators of the stress-induced enhancement of a primary immune response. Such enhancement during primary immunization may induce a long-term increase in immunologic memory resulting in subsequent augmentation of the immune response during secondary antigen exposure. Thus, the evolutionarily adaptive fight-or-flight stress response may protectively prepare the immune system for impending danger (e.g. infection and wounding by a predator), but may also contribute to stress-induced exacerbation of inflammatory and autoimmune diseases.

    View details for DOI 10.1093/intimm/dxh286

    View details for Web of Science ID 000230846800008

    View details for PubMedID 16000327

  • Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Viswanathan, K., Dhabhar, F. S. 2005; 102 (16): 5808-5813

    Abstract

    Effective immunoprotection requires rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. In contrast to immunosuppressive chronic stressors, short-term acute stressors have immunoenhancing effects. Here, we quantify leukocyte infiltration within a surgical sponge to elucidate the kinetics, magnitude, subpopulation, and chemoattractant specificity of an acute stress-induced increase in leukocyte trafficking to a site of immune activation. Mice acutely stressed before sponge implantation showed 200-300% higher neutrophil, macrophage, natural killer cell, and T cell infiltration than did nonstressed animals. We also quantified the effects of acute stress on lymphotactin- (LTN; a predominantly lymphocyte-specific chemokine), and TNF-alpha- (a proinflammatory cytokine) stimulated leukocyte infiltration. An additional stress-induced increase in infiltration was observed for neutrophils, in response to TNF-alpha, macrophages, in response to TNF-alpha and LTN, and natural killer cells and T cells in response to LTN. These results show that acute stress initially increases trafficking of all major leukocyte subpopulations to a site of immune activation. Tissue damage-, antigen-, or pathogen-driven chemoattractants subsequently determine which subpopulations are recruited more vigorously. Such stress-induced increases in leukocyte trafficking may enhance immunoprotection during surgery, vaccination, or infection, but may also exacerbate immunopathology during inflammatory (cardiovascular disease or gingivitis) or autoimmune (psoriasis, arthritis, or multiple sclerosis) diseases.

    View details for DOI 10.1073/pnas.0501650102

    View details for Web of Science ID 000228565200033

    View details for PubMedID 15817686

  • Good stress, bad stress and oxidative stress: Insights from anticipatory cortisol reactivity. Psychoneuroendocrinology Aschbacher, K., O'Donovan, A., Wolkowitz, O. M., Dhabhar, F. S., Su, Y., Epel, E. 2013; 38 (9): 1698-1708

    Abstract

    Chronic psychological stress appears to accelerate biological aging, and oxidative damage is an important potential mediator of this process. However, the mechanisms by which psychological stress promotes oxidative damage are poorly understood. This study investigates the theory that cortisol increases in response to an acutely stressful event have the potential to either enhance or undermine psychobiological resilience to oxidative damage, depending on the body's prior exposure to chronic psychological stress. In order to achieve a range of chronic stress exposure, forty-eight post-menopausal women were recruited in a case-control design that matched women caring for spouses with dementia (a chronic stress model) with similarly aged control women whose spouses were healthy. Participants completed a questionnaire assessing perceived stress over the previous month and provided fasting blood. Three markers of oxidative damage were assessed: 8-iso-prostaglandin F2α (IsoP), lipid peroxidation, 8-hydroxyguanosine (8-oxoG) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), reflecting oxidative damage to RNA/DNA respectively. Within approximately one week, participants completed a standardized acute laboratory stress task while salivary cortisol responses were measured. The increase from 0 to 30min was defined as "peak" cortisol reactivity, while the increase from 0 to 15min was defined as "anticipatory" cortisol reactivity, representing a cortisol response that began while preparing for the stress task. Women under chronic stress had higher 8-oxoG, oxidative damage to RNA (p<.01). A moderated mediation model was tested, in which it was hypothesized that heightened anticipatory cortisol reactivity would mediate the relationship between perceived stress and elevated oxidative stress damage, but only among women under chronic stress. Consistent with this model, bootstrapped path analysis found significant indirect paths from perceived stress to 8-oxoG and IsoP (but not 8-OHdG) via anticipatory cortisol reactivity, showing the expected relations among chronically stressed participants (p≤.01) Intriguingly, among those with low chronic stress exposure, moderate (compared to low) levels of perceived stress were associated with reduced levels of oxidative damage. Hence, this study supports the emerging model that chronic stress exposure promotes oxidative damage through frequent and sustained activation of the hypothalamic-pituitary-adrenal axis. It also supports the less studied model of 'eustress' - that manageable levels of life stress may enhance psychobiological resilience to oxidative damage.

    View details for DOI 10.1016/j.psyneuen.2013.02.004

    View details for PubMedID 23490070

  • Dysregulated relationship of inflammation and oxidative stress in major depression. Brain, behavior, and immunity Rawdin, B. J., Mellon, S. H., Dhabhar, F. S., Epel, E. S., PUTERMAN, E., Su, Y., Burke, H. M., Reus, V. I., Rosser, R., Hamilton, S. P., Nelson, J. C., Wolkowitz, O. M. 2013; 31: 143-152

    Abstract

    Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

    View details for DOI 10.1016/j.bbi.2012.11.011

    View details for PubMedID 23201587

  • Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors BRAIN BEHAVIOR AND IMMUNITY Kesler, S., Janelsins, M., Koovakkattu, D., Palesh, O., Mustian, K., Morrow, G., Dhabhar, F. S. 2013; 30: S109-S116

    Abstract

    Many survivors of breast cancer show significant cognitive impairments, including memory deficits. Inflammation induced by chemotherapy may contribute to hippocampal changes that underlie these deficits. In this cross-sectional study, we measured bilateral hippocampal volumes from high-resolution magnetic resonance images in 42 chemotherapy-treated breast cancer survivors and 35 healthy female controls. Patients with breast cancer were, on average, 4.8 ± 3.4 years off-therapy. In a subset of these participants (20 breast cancer, 23 controls), we quantified serum cytokine levels. Left hippocampal volumes and memory performance were significantly reduced and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF?) concentrations were significantly elevated in the breast cancer group compared to controls. In the breast cancer group, lower left hippocampal volume was associated with higher levels of TNF? and lower levels of IL-6 with a significant interaction between these two cytokines suggesting a potential modulatory effect of IL-6 on TNF?. Verbal memory performance was associated with cytokine levels and left hippocampal volume in both groups. These findings provide evidence of altered hippocampal volume and verbal memory difficulties following breast cancer chemotherapy that may be mediated by TNF? and IL-6.

    View details for DOI 10.1016/j.bbi.2012.05.017

    View details for Web of Science ID 000316510800013

    View details for PubMedID 22698992

  • Diurnal cortisol rhythm as a predictor of lung cancer survival BRAIN BEHAVIOR AND IMMUNITY Sephton, S. E., Lush, E., Dedert, E. A., Floyd, A. R., Rebholz, W. N., Dhabhar, F. S., Spiegel, D., Salmon, P. 2013; 30: S163-S170

    Abstract

    Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer.Lung cancer patients (n=62, 34 female) were within 5 years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis.The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively "flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=.009). Cortisol slope also predicted survival time from initial diagnosis (p=.012). Flattened profiles were linked with male gender (t=2.04, df=59, p=.046) and low total and cytotoxic T cell lymphocyte counts (r=-.39 and -.30, p=.004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival.Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

    View details for DOI 10.1016/j.bbi.2012.07.019

    View details for Web of Science ID 000316510800019

    View details for PubMedID 22884416

  • Stress, Coping, and Circadian Disruption Among Women Awaiting Breast Cancer Surgery ANNALS OF BEHAVIORAL MEDICINE Dedert, E., Lush, E., Chagpar, A., Dhabhar, F. S., Segerstrom, S. C., Spiegel, D., Dayyat, E., Daup, M., McMasters, K., Sephton, S. E. 2012; 44 (1): 10-20

    Abstract

    Psychological distress and coping related to a breast cancer diagnosis can profoundly affect psychological adjustment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for early mortality in metastatic colorectal and breast cancers, respectively.This study aims to explore the relationships of cancer-specific distress and avoidant coping with rest/activity and cortisol rhythm disruption in the period between diagnosis and breast cancer surgery.Fifty-seven presurgical breast cancer patients provided daily self-reports of cancer-specific distress and avoidant coping as well as actigraphic and salivary cortisol data.Distress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsistent rhythms). Patients with disrupted rest/activity cycles had flattened diurnal cortisol rhythms.Maladaptive psychological responses to breast cancer diagnosis were associated with disruption of circadian rest/activity rhythms. Given that circadian cycles regulate tumor growth, we need greater understanding of possible psychosocial effects in cancer-related circadian disruption.

    View details for DOI 10.1007/s12160-012-9352-y

    View details for Web of Science ID 000308822700005

    View details for PubMedID 22450856

  • Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length PHYSIOLOGY & BEHAVIOR Tomiyama, A. J., O'Donovan, A., Lin, J., Puterman, E., Lazaro, A., Chan, J., Dhabhar, F. S., Wolkowitz, O., Kirschbaum, C., Blackburn, E., Epel, E. 2012; 106 (1): 40-45

    Abstract

    Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three postmenopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol-saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening.

    View details for DOI 10.1016/j.physbeh.2011.11.016

    View details for Web of Science ID 000301910000006

    View details for PubMedID 22138440

  • Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response MOLECULAR PSYCHIATRY Wolkowitz, O. M., Mellon, S. H., Eper, E. S., Lin, J., Reus, V. I., Rosser, R., Burke, H., Compagnone, M., Nelson, J. C., Dhabhar, F. S., Blackburn, E. H. 2012; 17 (2): 164-172

    Abstract

    Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

    View details for DOI 10.1038/mp.2010.133

    View details for Web of Science ID 000299802400009

    View details for PubMedID 21242992

  • Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms BRAIN BEHAVIOR AND IMMUNITY Aschbacher, K., Epel, E., Wolkowitz, O. M., Prather, A. A., PUTERMAN, E., Dhabhar, F. S. 2012; 26 (2): 346-352

    Abstract

    Cognitive and affective responses to acute stress influence pro-inflammatory cytokine reactivity, and peripheral cytokines (particularly interleukin-1 beta (IL-1?)), can act on the brain to promote depressive symptoms. It is unknown whether acute stress-induced changes in positive affect and cognitions (POS) and pro-inflammatory reactivity predict future depressive symptoms. We examined acute stress responses among women, to determine prospective predictors of depressive symptoms. Hypotheses: (1) Stress-induced decreases in POS will be associated with stress-related increases in circulating IL-1?. (2) Acute stress-induced decreases in POS and increases in IL-1? reactivity will predict increases in depressive symptoms 1 year later. Thirty-five post-menopausal women were exposed to acute stress with the Trier Social Stress Task (TSST) and provided blood samples under resting conditions and 30 min after the conclusion of the TSST, which were assayed for IL-1?. IL-1? reactivity was quantified as post minus pre-TSST. Failure to maintain POS was quantified as the decrease in POS during the TSST. Change in depressive symptoms from the study baseline to the following year was determined. Greater acute stress-induced declines in POS were significantly associated with increased IL-1? reactivity (p?.02), which significantly predicted increases in depressive symptoms over the following year (p<.01), controlling for age, body mass index, chronic stress, antidepressant use and baseline depressive symptoms. IL-1? reactivity was a significant mediator of the relationship between POS decline and future increases in depressive symptoms (p=.04). Difficulty maintaining positivity under stress and heightened pro-inflammatory reactivity may be markers and/or mechanisms of risk for future increases in depressive symptoms.

    View details for DOI 10.1016/j.bbi.2011.10.010

    View details for Web of Science ID 000299805700019

    View details for PubMedID 22119400

  • Cumulative Inflammatory Load Is Associated with Short Leukocyte Telomere Length in the Health, Aging and Body Composition Study PLOS ONE O'Donovan, A., Pantell, M. S., Puterman, E., Dhabhar, F. S., Blackburn, E. H., Yaffe, K., Cawthon, R. M., Opresko, P. L., Hsueh, W., Satterfield, S., Newman, A. B., Ayonayon, H. N., Rubin, S. M., Harris, T. B., Epel, E. S. 2011; 6 (5)

    Abstract

    Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction.To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-? (TNF-?) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-? had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-? had significantly higher odds for short LTL compared with those who had neither high (OR?=?0.52, CI?=?0.37-0.72), only IL-6 high (OR?=?0.57, CI?=?0.39-0.83) or only TNF-? high (OR?=?0.67, CI?=?0.46-0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL.Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-?, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.

    View details for DOI 10.1371/journal.pone.0019687

    View details for Web of Science ID 000290558500023

    View details for PubMedID 21602933

  • Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings PLOS ONE Wolkowitz, O. M., Mellon, S. H., Epel, E. S., Lin, J., Dhabhar, F. S., Su, Y., Reus, V. I., Rosser, R., Burke, H. M., Kupferman, E., Compagnone, M., Nelson, J. C., Blackburn, E. H. 2011; 6 (3)

    Abstract

    Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of "accelerated aging" in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (?9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of "accelerated cell aging." Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.

    View details for DOI 10.1371/journal.pone.0017837

    View details for Web of Science ID 000288810500016

    View details for PubMedID 21448457

  • Position Statement Part two: Maintaining immune health EXERCISE IMMUNOLOGY REVIEW Walsh, N. P., Gleeson, M., Pyne, D. B., Nieman, D. C., Dhabhar, F. S., Shephard, R. J., Oliver, S. J., Bermon, S., Kajeniene, A. 2011; 17: 64-103

    Abstract

    The physical training undertaken by athletes is one of a set of lifestyle or behavioural factors that can influence immune function, health and ultimately exercise performance. Others factors including potential exposure to pathogens, health status, lifestyle behaviours, sleep and recovery, nutrition and psychosocial issues, need to be considered alongside the physical demands of an athlete's training programme. The general consensus on managing training to maintain immune health is to start with a programme of low to moderate volume and intensity; employ a gradual and periodised increase in training volumes and loads; add variety to limit training monotony and stress; avoid excessively heavy training loads that could lead to exhaustion, illness or injury; include non-specific cross-training to offset staleness; ensure sufficient rest and recovery; and instigate a testing programme for identifying signs of performance deterioration and manifestations of physical stress. Inter-individual variability in immunocompetence, recovery, exercise capacity, non-training stress factors, and stress tolerance likely explains the different vulnerability of athletes to illness. Most athletes should be able to train with high loads provided their programme includes strategies devised to control the overall strain and stress. Athletes, coaches and medical personnel should be alert to periods of increased risk of illness (e.g. intensive training weeks, the taper period prior to competition, and during competition) and pay particular attention to recovery and nutritional strategies. Although exercising in environmental extremes (heat, cold, altitude) may increase the stress response to acute exercise and elevate the extent of leukocyte trafficking it does not appear to have marked effects on immune function other than a depression of cell-mediated immunity when training at altitude. The available evidence does not support the contention that athletes training and competing in cold (or hot) conditions experience a greater reduction in immune function compared with thermoneutral conditions. Nevertheless, it remains unknown if athletes who regularly train and compete in cold conditions report more frequent, severe or longer-lasting infections. Research should identify whether the airway inflammation associated with breathing large volumes of cold dry air or polluted air impairs airway defences and whether athletes (and their physicians) wrongly interpret the sore throat symptoms that accompany exercising in cold or polluted air as an infection. Elite athletes can benefit from immunonutritional support to bolster immunity during periods of physiological stress. Ensuring adequate energy, carbohydrate and protein intake and avoiding deficiencies of micronutrients are key to maintaining immune health. Evidence is accumulating that some nutritional supplements including flavonoids such as quercetin and Lactobacillus probiotics can augment some aspects of immune function and reduce illness rates in exercise-stressed athletes. Limited data are non-supportive or mixed for use of N-3 polyunsaturated fatty acids, beta-glucans, bovine colostrums, ginseng, echinacea or megadoses of vitamin C by athletes. Relatively short periods of total sleep deprivation in humans (up to 3 consecutive nights without sleep) do not influence the risk of infection, and the reported increase in natural killer cell activity with this duration of total sleep deprivation would seem to rule out the possibility of an "open-window" for respiratory infections. Very little is known about the effects of more prolonged sleep disruption and repeated sleep disturbances on immune function and infection incidence, although recent studies have highlighted the importance of sleep quantity (total duration of sleep per night) and quality (number of awakenings per night) to protect against the common cold in healthy adults. Short- or long-term exercise can activate different components of a physiological stress response. Prolonged intense exercise may induce negative health consequences, many of which may be mediated by physiological pathways activated by chronic stress. Psychological stress is likely additive to the effects of physical stress and whereas short exposures to both physical or psychological stress can have a beneficial effect on immune function, chronic exposure to stress exerts detrimental effects on immune function and health. However, regular moderate exercise could be an important factor in ameliorating the negative health effects of chronic stress via the optimization and maintenance of the survival-promoting physiological changes induced by the short-term or acute stress response. Further research on mechanisms mediating the salubrious effects of exercise, and on the relationship between exercise and the psychosocial stress-status of an individual, is likely to be helpful for more fully and widely harnessing the health benefits of exercise. It is agreed by everyone that prevention of infection is always superior to treatment and this is particularly true in athletes residing in countries with limited medical facilities. Although there is no single method that completely eliminates the risk of contracting an infection, there are several effective ways of reducing the number of infectious episodes incurred over a given period. These means of reducing infection risk include appropriate management of training loads, use of appropriate recovery strategies, good personal hygiene, avoiding contact with large crowds, young children and sick people, good nutrition, getting adequate good quality sleep and limiting other life stresses to a minimum. Part two of the position statement includes sections on: training considerations (David Pyne); nutritional countermeasures to exercise-induced immune perturbations (David Nieman); effects of stress on immune function (Firdaus Dhabhar); sleep disruption and immune function (Roy Shephard); environmental extremes and the immune response to exercise (Neil Walsh and Samuel Oliver) and finally, prevention and treatment of common infections (Stéphane Bermon and Alma Kajeniene).

    View details for Web of Science ID 000288590500003

    View details for PubMedID 21446353

  • Sex Differences in Factors Influencing Recovery from Arthroscopic Knee Surgery CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Rosenberger, P. H., Dhabhar, F. S., Epel, E., Jokl, P., Ickovics, J. R. 2010; 468 (12): 3399-3405

    Abstract

    Many factors affect recovery from arthroscopic partial meniscectomy, including patient sex. However, sex differences in time to maximal recovery of knee function and factors influencing differential rates of recovery are unknown.We determined (1) preoperative sex differences, (2) sex differences in rate and extent of recovery through 1 year postoperatively, and (3) clinical and fitness variables that could explain potential sex differences in recovery from partial meniscectomy.The study sample consisted of 180 patients undergoing arthroscopic partial meniscectomy. Sex, age, body mass index, history of prior injury, length of time between knee injury/impairment and surgical evaluation, weekly exercise frequency, and self-reported fitness were assessed preoperatively, and extent of osteoarthritis was recorded postoperatively. We used the Tegner-Lysholm scale to assess knee function preoperatively and postoperatively at weeks 1, 3, 8, 16, 24, and 48 followups.Females had worse knee function and delayed maximal recovery, requiring 1 year, compared with males, who required only 4 months. History of prior knee injury and lower self-reported fitness were associated with slower recovery in females but not in males. Osteoarthritis was associated with slower recovery but not related to sex. Body mass index, length of time between injury/impairment and surgical evaluation, and weekly exercise frequency did not influence rate of recovery.Females have delayed recovery after arthroscopic partial meniscectomy. Prior knee injury and self-reported low fitness are associated with delayed recovery for females but not for males.

    View details for DOI 10.1007/s11999-010-1562-7

    View details for Web of Science ID 000288440700036

    View details for PubMedID 20848242

  • Regulation of circadian rhythms and hypothalamic-pituitary-adrenal axis: an overlooked interaction in cancer LANCET ONCOLOGY Innominato, P. F., Palesh, O., Dhabhar, F. S., Levi, F., Spiegel, D. 2010; 11 (9): 816-817

    View details for Web of Science ID 000282412000011

    View details for PubMedID 20816374

  • Dynamics of telomerase activity in response to acute psychological stress BRAIN BEHAVIOR AND IMMUNITY Epel, E. S., Lin, J., Dhabhar, F. S., Wolkowitz, O. M., PUTERMAN, E., Karan, L., Blackburn, E. H. 2010; 24 (4): 531-539

    Abstract

    Telomerase activity plays an essential role in cell survival, by lengthening telomeres and promoting cell growth and longevity. It is now possible to quantify the low levels of telomerase activity in human leukocytes. Low basal telomerase activity has been related to chronic stress in people and to chronic glucocorticoid exposure in vitro. Here we test whether leukocyte telomerase activity changes under acute psychological stress. We exposed 44 elderly women, including 22 high stress dementia caregivers and 22 matched low stress controls, to a brief laboratory psychological stressor, while examining changes in telomerase activity of peripheral blood mononuclear cells (PBMCs). At baseline, caregivers had lower telomerase activity levels than controls, but during stress telomerase activity increased similarly in both groups. Across the entire sample, subsequent telomerase activity increased by 18% one hour after the end of the stressor (p<0.01). The increase in telomerase activity was independent of changes in numbers or percentages of monocytes, lymphocytes, and specific T cell types, although we cannot fully rule out some potential contribution from immune cell redistribution in the change in telomerase activity. Telomerase activity increases were associated with greater cortisol increases in response to the stressor. Lastly, psychological response to the tasks (greater threat perception) was also related to greater telomerase activity increases in controls. These findings uncover novel relationships of dynamic telomerase activity with exposure to an acute stressor, and with two classic aspects of the stress response - perceived psychological stress and neuroendocrine (cortisol) responses to the stressor.

    View details for DOI 10.1016/j.bbi.2009.11.018

    View details for Web of Science ID 000277206600004

    View details for PubMedID 20018236

  • Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions BRAIN BEHAVIOR AND IMMUNITY Fredericks, C. A., Drabant, E. M., Edge, M. D., Tillie, J. M., Hallmayer, J., Ramel, W., Kuo, J. R., Mackey, S., Gross, J. J., Dhabhar, F. S. 2010; 24 (3): 350-357

    Abstract

    The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.

    View details for DOI 10.1016/j.bbi.2009.10.014

    View details for Web of Science ID 000275217300004

    View details for PubMedID 19883751

  • Healthy young women with serotonin transporter SS Polymorphism show a pro-inflammatory bias under resting & stress conditions Brain, behavior, and Immunity Fredericks, C., Drabant, E.M., Edge, M.D., Tillie, J.M., Hallmayer, J...., Mackey, S., Gross, J.J, Dhabhar, F.S. 2010; 24: 350-357
  • Surgical stress-induced immune cell redistribution profiles predict short-term and long-term postsurgical recovery. A prospective study. journal of bone and joint surgery. American volume Rosenberger, P. H., Ickovics, J. R., Epel, E., Nadler, E., Jokl, P., Fulkerson, J. P., Tillie, J. M., Dhabhar, F. S. 2009; 91 (12): 2783-2794

    Abstract

    The experience of undergoing surgery is known to induce a short-term, fight-or-flight physiological stress response. As an optimum immune response at the site of surgery would enhance tissue repair, we examined surgical stress-induced immune cell redistribution profiles as predictors, and potential mediators, of short and long-term postoperative recovery. We tested the a priori hypothesis that predefined adaptive immune cell redistribution profiles observed during surgery will predict enhanced postoperative recovery.This prospective longitudinal study involved fifty-seven patients undergoing meniscectomy. Knee function was assessed preoperatively and at one, three, eight, sixteen, twenty-four, and forty-eight weeks postoperatively with use of the clinically validated Lysholm scale, which assesses mechanical function, pain, mobility, and the ability to perform daily activities. Surgery-induced immune cell redistribution was measured in the blood at baseline, before surgery, and after surgery.Mixed-model repeated-measures analyses revealed a main effect of immune cell redistribution: patients who showed the predefined "adaptive" lymphocyte and monocyte redistribution profiles during surgery showed enhanced recovery. Interesting differences were also observed between the sexes: women as a group showed less adaptive redistribution and correspondingly showed significantly delayed maximum recovery, requiring forty-eight weeks, compared with men, who required only sixteen weeks. Inter-individual differences in leukocyte redistribution predicted the rate of recovery across both sexes.Immune cell redistribution that is induced by the stress of undergoing surgery can predict (and may partially mediate) postoperative healing and recovery. These findings may provide the basis for identifying patients (either prospectively or during surgery) who are likely to show good as opposed to poor recovery following surgery and for designing interventions that would maximize protective immune responses and enhance the rate and extent of recovery.

    View details for DOI 10.2106/JBJS.H.00989

    View details for PubMedID 19952239

  • Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer BRAIN BEHAVIOR AND IMMUNITY Sephton, S. E., Dhabhar, F. S., Keuroghlian, A. S., Giese-Davis, J., McEwen, B. S., Ionan, A. C., Spiegel, D. 2009; 23 (8): 1148-1155

    Abstract

    Cancer treatment is known to have significant immuno-suppressive/dysregulatory effects. Psychological distress and depression, which often accompany cancer diagnosis and treatment, can also suppress or dysregulate endocrine and immune function. Cell-mediated immunity (CMI) is critical for protection against a host of pathogens to which cancer patients may be particularly susceptible. CMI is also important for defense against some tumors. This study explored relationships among depressive symptoms, cortisol secretion, and CMI responses in 72 women with metastatic breast cancer. Depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression Scale (CES-D). Saliva was sampled throughout the day over a 3-day period to obtain a physiologic index of diurnal cortisol concentrations and rhythmicity, which is associated with breast cancer survival time. CMI for specific antigens was measured following intradermal administration of seven commonly encountered antigens (tuberculin, tetanus, diphtheria, Streptococcus, Candida, Trichophyton, and Proteus). Analyses adjusting for relevant medical and treatment variables indicated that women reporting more depressive symptoms showed suppressed immunity as measured by lower average induration size. Women with higher mean diurnal cortisol concentrations also showed suppressed immunity as indicated by a decreased number of antigens to which positive reactions were measured. This study highlights the relationships among depression, stress, and immune function in the context of advanced breast cancer.

    View details for DOI 10.1016/j.bbi.2009.07.007

    View details for Web of Science ID 000271754700016

    View details for PubMedID 19643176

  • Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression JOURNAL OF PSYCHIATRIC RESEARCH Dhabhar, F. S., Burke, H. M., Epel, E. S., Mellon, S. H., Rosser, R., Reus, V. I., Wolkowitz, O. M. 2009; 43 (11): 962-969

    Abstract

    Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and disorders involving chronic inflammation are often co-morbid with major depression. Since healthy immune regulation is accomplished through counter-balancing effects of pro- and anti-inflammatory cytokines, we hypothesized that depressed subjects (compared to controls) would express lower concentrations of the anti-inflammatory/immunoregulatory cytokine interleukin (IL)-10, and a higher IL-6/IL-10 ratio. We also examined the possibility that depressed subjects may exhibit a deficiency in the regulatory loop involving IL-6 induced secretion of IL-10. Therefore, we hypothesized that circulating IL-6 and IL-10 would be positively correlated in controls, while the correlation would be weaker in depressed subjects. Resting state serum cytokine concentrations were quantified in 12 unmedicated depressed subjects, and 11 age, gender, and ethnicity-matched controls. Depressed subjects showed significantly lower IL-10 (p=0.03, Cohen's d=-0.96), non-significantly higher IL-6, and significantly higher IL-6/IL-10 ratios (p=0.05, Cohen's d=0.50). Across all participants, higher scores on the self-rated Inventory of Depressive Symptoms were associated with lower IL-10 (r(21)=-0.57, p=0.005) and non-significantly higher IL-6/IL-10 ratios (r(21)=0.38, p=0.07), but not related to IL-6 concentrations. As hypothesized, IL-6 and IL-10 concentrations were strongly and positively correlated in controls (r(9)=0.81, p=0.003), but were completely dissociated in depressed subjects (r(10)=0.01, p=0.98). These results suggest that lower IL-10 levels, a higher IL-6/IL-10 ratio, and the apparent absence of a counter-balancing, immunoregulatory increase in IL-10 in response to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression. Therefore, reduced induction/availability of IL-10, that would normally inhibit pro-inflammatory cytokine actions and resolve inflammation, may contribute to the depressogenic as well as the inflammatory disease-promoting effects of chronic, low-level elevations in pro-inflammatory cytokines.

    View details for DOI 10.1016/j.jpsychires.2009.05.010

    View details for Web of Science ID 000268287100002

    View details for PubMedID 19552919

  • Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women BRAIN BEHAVIOR AND IMMUNITY O'Donovan, A., Lin, J., Dhabhar, F. S., Wolkowitz, O., Tillie, J. M., Blackburn, E., Epel, E. 2009; 23 (4): 446-449

    Abstract

    The combination of less positive and more negative expectations for the future (i.e., lower optimism and higher pessimism) increases risk for disease and early mortality. We tested the possibility that expectancies might influence health outcomes by altering the rate of biological aging, specifically of the immune system (immunosenescence). However, no studies to date have examined associations between optimism or pessimism and indicators of immunosenescence such as leukocyte telomere length (TL) and interleukin-6 (IL-6) levels. We investigated whether dispositional tendencies towards optimism and pessimism were associated with TL and IL-6 in a sample of 36 healthy post-menopausal women. Multiple regression analyses where optimism and pessimism were entered simultaneously, and chronological age and caregiver status were controlled, indicated that pessimism was independently associated with shorter TL (beta=-.68, p=.001) and higher IL-6 concentrations (beta=.50, p=.02). In contrast, optimism was not independently associated with either measure of immunosenescence. These findings suggest that dispositional pessimism may increase IL-6 and accelerate rate of telomere shortening. Mechanistic causal relationships between these parameters need to be investigated.

    View details for DOI 10.1016/j.bbi.2008.11.006

    View details for Web of Science ID 000265239800007

    View details for PubMedID 19111922

  • Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection and Immunopathology NEUROIMMUNOMODULATION Dhabhar, F. S. 2009; 16 (5): 300-317

    Abstract

    Stress is known to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate asthma, and allergic, autoimmune and inflammatory diseases, although such diseases should be ameliorated by immunosuppression. Moreover, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that enables the cardiovascular and musculoskeletal systems to promote survival, and it is unlikely that this response would suppress immune function at a time when it is most required for survival (e.g. in response to wounding and infection by a predator or aggressor). These observations suggest that stress may suppress immune function under some conditions while enhancing it under others. The effects of stress are likely to be beneficial or harmful depending on the type (immunoprotective, immunoregulatory/inhibitory, or immunopathological) of immune response that is affected. Studies have shown that several critical factors influence the direction (enhancing vs. suppressive) of the effects of stress or stress hormones on immune function: (1) Duration (acute vs. chronic) of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or long-term stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immunoenhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response. We propose that it is important to study and, if possible, to clinically harness the immunoenhancing effects of the acute stress response, that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. In view of the ubiquitous nature of stress and its significant effects on immunoprotection as well as immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside.

    View details for DOI 10.1159/000216188

    View details for Web of Science ID 000267648300006

    View details for PubMedID 19571591

  • Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection versus Immunopathology. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Dhabhar, F. S. 2008; 4 (1): 2-11

    Abstract

    : It is widely believed that stress suppresses immune function and increases susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate allergic, autoimmune, and inflammatory diseases. These observations suggest that stress may have bidirectional effects on immune function, being immunosuppressive in some instances and immunoenhancing in others. It has recently been shown that in contrast to chronic stress that suppresses or dysregulates immune function, acute stress can be immunoenhancing. Acute stress enhances dendritic cell, neutrophil, macrophage, and lymphocyte trafficking, maturation, and function and has been shown to augment innate and adaptive immune responses. Acute stress experienced prior to novel antigen exposure enhances innate immunity and memory T-cell formation and results in a significant and long-lasting immunoenhancement. Acute stress experienced during antigen reexposure enhances secondary/adaptive immune responses. Therefore, depending on the conditions of immune activation and the immunizing antigen, acute stress may enhance the acquisition and expression of immunoprotection or immunopathology. In contrast, chronic stress dysregulates innate and adaptive immune responses by changing the type 1-type 2 cytokine balance and suppresses immunity by decreasing leukocyte numbers, trafficking, and function. Chronic stress also increases susceptibility to skin cancer by suppressing type 1 cytokines and protective T cells while increasing suppressor T-cell function. We have suggested that the adaptive purpose of a physiologic stress response may be to promote survival, with stress hormones and neurotransmitters serving as beacons that prepare the immune system for potential challenges (eg, wounding or infection) perceived by the brain (eg, detection of an attacker). However, this system may exacerbate immunopathology if the enhanced immune response is directed against innocuous or self-antigens or dysregulated following prolonged activation, as seen during chronic stress. In view of the ubiquitous nature of stress and its significant effects on immunoprotection and immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside.

    View details for DOI 10.1186/1710-1492-4-1-2

    View details for PubMedID 20525121

  • Gonadal hormone-dependent and -independent regulation of immune function by photoperiod in Siberian hamsters AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Prendergast, B. J., Baillie, S. R., Dhabhar, F. S. 2008; 294 (2): R384-R392

    Abstract

    Siberian hamsters (Phodopus sungorus) exhibit changes in reproductive and immune function in response to seasonal variations in day length. Exposure to short days induces gonadal regression and inhibits testosterone secretion. In parallel, short days enhance immune function: increasing leukocyte numbers and attenuating cytokine and behavioral responses to infection. We examined whether photoperiodic changes in leukocyte phenotypes and sickness behaviors are dependent on concurrent photoperiodic changes in gonadal function. Male hamsters were gonadectomized or sham-gonadectomized and either exposed to short days (9 h light/day; SD) or kept in their natal long-day (15 h light/day; LD) photoperiod for 10-13 wk. Blood samples were obtained for leukocyte enumeration, and hamsters were challenged with bacterial LPS, which induced behavioral (anorexia, reductions in nest building) and somatic (weight loss) sickness responses. Among gonad-intact hamsters, exposure to SD increased total and CD62L+ lymphocytes and CD3+ T lymphocytes in blood and significantly attenuated LPS-induced sickness responses. Independent of photoperiod, castration alone increased total and CD62L+ lymphocyte and CD3+ T lymphocyte numbers and attenuated somatic and anorexic sickness responses. Among castrated hamsters, SD exposure increased lymphocyte numbers and suppressed sickness behaviors. In castrated hamsters, the magnitude of most immunological effects of SD were diminished relative to those evident in gonad-intact hamsters. The SD phenotype in several measures of immunity can be instated via elimination of gonadal hormones alone; however, photoperiodic effects on immune function persist even in castrated hamsters. Thus, photoperiod affects the immune system and neural-immune interactions underlying sickness behaviors via gonadal hormone-dependent and -independent mechanisms.

    View details for DOI 10.1152/ajpregu.00551.2007

    View details for Web of Science ID 000252772800013

    View details for PubMedID 17989142

  • Stressor-specific alterations in corticosterone and immune responses in mice BRAIN BEHAVIOR AND IMMUNITY Bowers, S. L., Bilbo, S. D., Dhabhar, F. S., Nelson, R. J. 2008; 22 (1): 105-113

    Abstract

    Different stressors likely elicit different physiological and behavioral responses. Previously reported differences in the effects of stressors on immune function may reflect qualitatively different physiological responses to stressors; alternatively, both large and subtle differences in testing protocols and methods among laboratories may make direct comparisons among studies difficult. Here we examine the effects of chronic stressors on plasma corticosterone concentrations, leukocyte redistribution, and skin delayed-type hypersensitivity (DTH), and the effects of acute stressors on plasma corticosterone and leukocyte redistribution. The effects of several commonly used laboratory stressors including restraint, forced swim, isolation, and low ambient temperatures (4 degrees C) were examined. Exposure to each stressor elevated corticosterone concentrations, with restraint (a putative psychological stressor) evoking a significantly higher glucocorticoid response than other stressors. Chronic restraint and forced swim enhanced the DTH response compared to the handled, low temperature, or isolation conditions. Restraint, low temperature, and isolation significantly increased trafficking of lymphocytes and monocytes compared to forced swim or handling. Generally, acute restraint, low temperature, isolation, and handling increased trafficking of lymphocytes and monocytes. Considered together, our results suggest that the different stressors commonly used in psychoneuroimmunology research may not activate the physiological stress response to the same extent. The variation observed in the measured immune responses may reflect differential glucocorticoid activation, differential metabolic adjustments, or both processes in response to specific stressors.

    View details for DOI 10.1016/j.bbi.2007.07.012

    View details for Web of Science ID 000252375800016

    View details for PubMedID 17890050

  • Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague-Dawley rats JOURNAL OF PROTEOME RESEARCH Teague, C. R., Dhabhar, F. S., Barton, R. H., Beckwith-Hall, B., Powell, J., Cobain, M., Singer, B., McEwen, B. S., Lindon, J. C., Nicholson, J. K., Holmes, E. 2007; 6 (6): 2080-2093

    Abstract

    The biochemical effects of acute and chronic psychological stress have been investigated in male Sprague-Dawley rats using a combination of 1H NMR spectral analysis of plasma and conventional hematological analyses. Animals were subjected to 35 consecutive days of 6-h sessions of stress, and following a 9 day break, were stressed for a further 6-h period. Plasma samples were collected at 0, 1, 3, and 6 h on days 1, 9, 21, 35, and 44, measured using 600 MHz 1H NMR spectroscopy, and analyzed by Principal Components Analysis. Time-dependent biochemical effects of psychological stress on a range of endogenous metabolites were evident and were correlated with the intensity of the stress response as defined by corticosterone and hematological parameters. Following acute stress, increases in the levels of glucose and ketone bodies, and decreases in the levels of acetate, alanine, isoleucine, lactate, leucine, valine, and lipoproteins, were observed. Chronic stress-induced increases in plasma levels of alanine, lactate (day 9), and leucine, valine, and choline (day 44) and decreases in acetate (day 9) and lipoprotein concentrations were observed. Positive correlations between plasma corticosterone level and glucose and glycerol, and between plasma lipoprotein concentrations and hemoglobin levels, were established using Projection to Latent Structures (PLS) analysis. This study indicates the potential of using NMR-based metabonomic strategies for the characterization of endogenous metabolic perturbations induced by psychological stressors and lifestyle choices.

    View details for DOI 10.1021/pr060412s

    View details for Web of Science ID 000246893500003

    View details for PubMedID 17474765

  • Pineal-dependent and -independent effects of photoperiod on immune function in Siberian hamsters (Phodopus sungorus) HORMONES AND BEHAVIOR Wen, J. C., Dhabhar, F. S., Prendergast, B. J. 2007; 51 (1): 31-39

    Abstract

    Siberian hamsters (Phodopus sungorus) exhibit reproductive and immunological responses to photoperiod. Short (<10-h light/day) days induce gonadal atrophy, increase leukocyte concentrations, and attenuate thermoregulatory and behavioral responses to infection. Whereas hamster reproductive responses to photoperiod are dependent on pineal melatonin secretion, the role of the pineal in short-day induced changes in immune function is not fully understood. To examine this, adult hamsters were pinealectomized (PINx) or sham-PINx, and transferred to short days (9-h light/day; SD) or kept in their natal long-day (15-h light/day; LD) photoperiod. Intact and PINx hamsters housed in LD maintained large testes over the next 12 weeks; sham-PINx hamsters exhibited gonadal regression in SD, and PINx abolished this effect. Among pineal-intact hamsters, blood samples revealed increases in leukocyte, lymphocyte, CD62L+ lymphocyte, and T cell counts in SD relative to LD; PINx did not affect leukocyte numbers in LD hamsters, but abolished the SD increase in these measures. Hamsters were then treated with bacterial lipopolysaccharide (LPS), which induced thermoregulatory (fever), behavioral (anorexia, reductions in nest building), and somatic (weight loss) sickness responses in all groups. Among pineal-intact hamsters, febrile and behavioral responses to LPS were attenuated in SD relative to LD. PINx did not affect sickness responses to LPS in LD hamsters, but abolished the ameliorating effects of SD on behavioral responses to LPS. Surprisingly, PINx failed to abolish the effect of SD on fever. In common with the reproductive system, PINx induces the LD phenotype in most aspects of the immune system. The pineal gland is required for photoperiodic regulation of circulating leukocytes and neural-immune interactions that mediate select aspects of sickness behaviors.

    View details for DOI 10.1016/j.yhbeh.2006.08.001

    View details for Web of Science ID 000243645100005

    View details for PubMedID 17022983

  • The adrenal gland is a source of stress-induced circulating IL-18 JOURNAL OF NEUROIMMUNOLOGY Sugama, S., Wang, N., Shimokawa, N., Koibuchi, N., Fujita, M., Hashimoto, M., Dhabhar, F. S., Conti, B. 2006; 172 (1-2): 59-65

    Abstract

    The present study compared plasma IL-18 levels between sham-operated and adrenalectomized mice following stress to investigate whether the adrenal gland contributes to the elevation of circulating IL-18 during stress. Two hours of stress provoked a robust, stressor-dependent, elevation of IL-18 mRNA and peptide in the adrenal gland in sham-operated mice. Consistently, levels of circulating mature IL-18 increased during stress and remained elevated for up to 6 h after stress. The stress-induced increase in circulating IL-18 was abolished by adrenalectomy. These findings demonstrate that the adrenal gland is required to achieve elevation of circulating IL-18 during stress.

    View details for DOI 10.1016/j.jneuroim.2005.11.001

    View details for Web of Science ID 000236266900006

    View details for PubMedID 16359733

  • Immune function in PTSD PSYCHOBIOLOGY OF POSTTRAUMATIC STRESS DISORDER: A DECADE OF PROGRESS Altemus, M., Dhabhar, F. S., Yang, R. 2006; 1071: 167-183

    Abstract

    Disturbed regulation of both the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenomedullary system in posttraumatic stress disorder (PTSD) suggests that immune function, which is modulated by these systems, may also be dysregulated. Two dermatologic, in vivo measures of immune function, delayed-type hypersensitivity (DTH) and skin barrier function recovery, were examined in female subjects with PTSD and compared to measures in healthy female comparison subjects. In addition, at the time of DTH test placement, circulating numbers of lymphocyte subtypes were assessed. In separate studies, the effects of acute psychological stress on DTH and skin barrier function recovery were examined in healthy volunteer subjects. Both DTH and barrier function recovery were enhanced in women with PTSD. These findings contrast with the effects of acute stress in healthy control subjects, which was associated with suppression of DTH responses and skin barrier function recovery. There was no difference between subjects with PTSD and healthy control subjects in proportions of circulating lymphocyte subsets or in expression of the lymphocyte markers CD62, CD25, and CD45RO/CD45RA. These results suggest that cell-mediated immune function is enhanced in individuals with PTSD, a condition that imposes chronic physiologic and mental stress on sufferers. These findings contrast with suppression of DTH and skin barrier function recovery in healthy volunteers in response to acute psychological stress.

    View details for DOI 10.1196/annals.1364.013

    View details for Web of Science ID 000240653600013

    View details for PubMedID 16891569

  • A biobehavioral perspective of tumor biology. Discovery medicine McDonald, P. G., Antoni, M. H., Lutgendorf, S. K., Cole, S. W., Dhabhar, F. S., Sephton, S. E., Stefanek, M., Sood, A. K. 2005; 5 (30): 520-526

    Abstract

    Extract: The perspective that cancer may be causally linked to stress has a long history. In 200 AD, Galen proposed that melancholic women were more susceptible to cancer than women who were sanguine. Rigorous examinations of related observations have lagged over the ensuing centuries. More recently, epidemiologic studies have shown that psychologic and social characteristics (e.g., chronic stress and negative life events, social isolation and support, socioeconomic burden, and emotional processes) might be associated with differential cancer incidence, progression, and mortality. The biologic mechanisms (e.g., signaling pathways) that may account for such observations are being discovered through the convergence of relevant molecular, cellular, and clinical data. In this article, we review the clinical and experimental evidence regarding the effects of stress on tumor development, growth, and progression. Within this context, we define "stress" as an external event ("stressor") or perception of such events that engender psychologic and physiologic changes ("stress responses") designed to approach, avoid, or defend against the external event.

    View details for PubMedID 20704834

  • Skeleton photoperiods alter delayed-type hypersensitivity responses and reproductive function of Siberian hamsters (Phodopus sungorus) JOURNAL OF NEUROENDOCRINOLOGY Gatien, M. L., Hotchkiss, A. K., Dhabhar, F. S., Nelson, R. J. 2005; 17 (11): 733-739

    Abstract

    Photoperiod (day length) can modulate immune function. Whether these photoperiodic effects on immune function are mediated directly by a circadian photoperiodic time measurement system or indirectly by nonspecific (e.g. stressful) effects of light is unknown. To discriminate between these two possibilities, Siberian hamsters (Phodopus sungorus) were housed in either long or short photoperiods (LD 16 : 8 h or LD 8 : 16 h) or in 'skeleton' long or short photoperiods (LD 1 : 14 h: LD 1 : 8 h or LD 1 : 6 h: LD 1 : 16 h). In the skeleton photoperiods, both long- and short-day animals received 2 h of light per day. After 10 weeks in their respective photoperiods, hamsters were tested for an antigen specific immune response using a delayed type hypersensitivity (DTH) model. Reproductive and endocrine responses of hamsters in each of the skeleton photoperiods were equivalent to those in standard long or short days, respectively. Hamsters in skeleton short days and LD 8 : 16 increased DTH responses compared to hamsters in both long-day groups. DTH responses were equivalent in both long-day groups. These results suggest that the influences of day length on immune function potentially are due to circadian photoperiodic time measurement systems.

    View details for DOI 10.1111/j.1365-2826.2005.01371.x

    View details for Web of Science ID 000232494000006

    View details for PubMedID 16219002

  • Stress-induced modulation of NK activity during influenza viral infection: role of glucocorticoids and oploids BRAIN BEHAVIOR AND IMMUNITY Tseng, R. J., Padgett, D. A., Dhabhar, F. S., Engler, H., Sheridan, J. F. 2005; 19 (2): 153-164

    Abstract

    Activation of the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system by stress has been shown to modulate both innate and adaptive immunity during an experimental influenza A/PR8 viral infection. HPA activation alters levels of glucocorticoids (GC) and opioids which are associated with suppression of lymphoid cellularity and NK activity. These experiments were designed to investigate the role that stress-induced GC and opioids have in modulating NK activity during an influenza viral infection. C57BL/6 mice were treated daily with mifepristone (RU486), a GC receptor antagonist or naltrexone (NTX), a non-specific opioid receptor antagonist. Mice were infected intranasally with A/PR8 virus and underwent daily restraint stress (RST). Phenotypic analysis of splenic cell populations and NK cytotoxicity were assessed at 3 days post-infection. RST of infected mice significantly suppressed splenic CD3(-)DX5+ cellularity and NK cytolytic activity. RU486 administration fully restored splenic NK cellularity but not cytolytic activity. NTX administration restored NK cytolytic activity but not splenic NK cell number. A similar restoration in NK cytolytic activity was observed after administration of beta-funaltrexamine (FNA), a mu-specific opioid receptor antagonist, but not the delta- or kappa-specific opioid receptor antagonists naltrindole or nor-binaltorphimine, respectively. Co-administration of RU486 and NTX restored both NK cellularity and cytolytic activity. The restoration of RST-induced suppression of NK activity by RU486 and NTX or FNA suggests that glucocorticoids modulate NK cellularity and opioids that bind to the mu-opioid receptor modulate NK cytotoxicity during periods of stress and viral infection.

    View details for DOI 10.1016/j.bbi.2004.07.001

    View details for Web of Science ID 000226761600008

    View details for PubMedID 15664788

  • How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis ARTHRITIS AND RHEUMATISM Straub, R. H., Dhabhar, F. S., Bijlsma, J. W., Cutolo, M. 2005; 52 (1): 16-26

    View details for DOI 10.1002/art.20747

    View details for Web of Science ID 000226507700004

    View details for PubMedID 15641084

  • Accelerated telomere shortening in response to life stress PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D., Cawthon, R. M. 2004; 101 (49): 17312-17315

    Abstract

    Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.

    View details for Web of Science ID 000225740100059

    View details for PubMedID 15574496

  • Modulation of natural killer cell activity by restraint stress during an influenza A/PR8 infection in mice BRAIN BEHAVIOR AND IMMUNITY Hunzeker, J., Padgett, D. A., Sheridan, P. A., Dhabhar, F. S., Sheridan, J. F. 2004; 18 (6): 526-535

    Abstract

    These experiments were designed to examine the influences of restraint stress (RST) on natural killer (NK) activity and to determine its consequences on influenza A/PR8 (A/PR8) viral replication in mice. The data showed that RST delayed the recruitment of NK1.1+ cells into the lung parenchyma during infection. Quantification of MIP-1alpha and MCP-1 gene expression by real-time PCR revealed that RST suppressed the chemokines responsible for NK cell recruitment into the infected tissue. Additionally, RST suppressed the expression of several macrophage-derived cytokines involved in the effector response of NK cells. IL-15, which is the main cytokine involved in NK cell development and homeostasis, and IL-12, which is important for NK cytotoxicity, were both suppressed. As the NK cell response is an important innate response to control viral replication, we hypothesized that the RST-mediated reduction in NK cell numbers and function would enable viral replication to continue unchecked. In fact, there was enhanced viral replication in the lungs of RST animals. Interestingly, expression of the anti-viral type I interferons (IFN-alpha and IFN-beta) was elevated presumably in response to the elevated viral load in the stressed mice. Together, these data show that RST suppressed expression of the cytokine genes involved in the recruitment and activation of NK cells during an experimental influenza viral infections. The consequence of this effect was diminished NK cell function and enhanced viral replication.

    View details for DOI 10.1016/j.bbi.2003.12.010

    View details for Web of Science ID 000224313900006

    View details for PubMedID 15331123

  • Immune and stress responses in C57BL/6 and C3H/HeN mouse strains following photoperiod manipulation NEUROENDOCRINOLOGY LETTERS Gatien, M. L., Hotchkiss, A. K., Neigh, G. N., Dhabhar, F. S., Nelson, R. J. 2004; 25 (4): 267-272

    Abstract

    The purpose of this study was to determine whether two different strains of mice, that are reproductively unresponsive to photoperiod, adjust immune function in response to photoperiod.Adult male C3H/HeN (C3H) and C57BL/6 (C57) mice were each placed into either a long (LD 16:8) or short (LD 8:16) photoperiod for 10 weeks (n = 15/ group).Blood was collected for flow cytometry and radioimmunoassay analysis of leukocyte numbers and corticosterone concentrations, respectively. In addition, all mice were sensitized to, and challenged with the antigen, 2,4-dinitro-1-fluorobenzene. Pinnae measurements were obtained for 7 days following challenge to determine the magnitude of the inflammatory response.Photoperiod did not affect leukocyte cell numbers in either C3H or C57 mice. C3H mice displayed higher neutrophil numbers than C57 mice (p< 0.0001), whereas C57 mice displayed higher lymphocyte numbers than C3H mice (p< 0.01). C3H mice housed in LD 16:8 had higher corticosterone concentrations than those housed in LD 8:16 (p< 0.005) and C57 mice housed in either photoperiod (p< 0.05). Photoperiod did not affect the inflammatory response, though C57 mice displayed an overall higher magnitude of response than C3H mice (p<0.05).Our results suggest that photoperiod does not alter immune function in C3H and C57 mice. Strain differences in immune function, however, were observed.Immune function is unresponsive to photoperiod in these laboratory mice, possibly indicating; a link between immune and reproductive responsiveness to photoperiod, the decreased predictive value of this annual cue to domesticated animals, or both.

    View details for Web of Science ID 000224464200005

    View details for PubMedID 15361815

  • Effects of photoperiod history on immune responses to intermediate day lengths in Siberian hamsters (Phodopus sungorus) JOURNAL OF NEUROIMMUNOLOGY Prendergast, B. J., Bilbo, S. D., Dhabhar, F. S., Nelson, R. J. 2004; 149 (1-2): 31-39

    Abstract

    Seasonal changes in day length enhance or suppress immune function in individuals of several mammalian species. Siberian hamsters (Phodopus sungorus) are long-day breeders that adjust reproductive physiology and behavior, body mass, and immune function following exposure to short photoperiods. Photoperiods of intermediate-duration, encountered in nature by juvenile hamsters born in early-spring and by those born in mid-summer, trigger gonadal development in the former cohort and inhibit the onset of puberty in the latter. Divergent reproductive responses to the same intermediate photoperiod depend on a photoperiod history, communicated during gestation. These experiments assessed whether photoperiod history during gestation likewise impacts immunological responses to intermediate photoperiods. Male hamsters were gestated in long photoperiods and remained in long photoperiods postnatally, or were transferred to an intermediate-duration or a short-duration photoperiod; other males were gestated in short days and transferred to an intermediate-duration photoperiod at birth. Long days stimulated, and short days inhibited, somatic and reproductive development; intermediate day lengths either accelerated or inhibited somatic and reproductive development, depending on whether hamsters were gestated in short days or long days, respectively. By contrast, photoperiod during gestation did not affect most immune endpoints. The data suggest that photoperiodic mechanisms that enhance and suppress several aspects of immunity in young-adult hamsters are not responsive to prenatally communicated photoperiod history information.

    View details for DOI 10.1016/j.jneuroim.2003.12.006

    View details for Web of Science ID 000220653300004

    View details for PubMedID 15020062

  • Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Dinkel, K., Dhabhar, F. S., Sapolsky, R. M. 2004; 101 (1): 331-336

    Abstract

    Many neurological insults and neurodegenerative disorders are accompanied by an acute inflammatory reaction that can contribute to neuronal damage. This inflammation involves infiltration of bloodborne polymorphonuclear leukocytes (PMNs) into the injured brain area. The role of inflammation in brain injury, however, is controversial, because recent studies suggest that inflammation may actually be beneficial in the recovery from brain damage. Therefore, we investigated the effects of pathophysiologically relevant concentrations of PMNs in vitro on mixed hippocampal primary cultures. Rat PMNs and peripheral blood lymphocytes were isolated by density centrifugation and cocultured with hippocampal cells for 24-72 h plus or minus an excitotoxic insult (50 microM kainic acid) or 6-h oxygen glucose deprivation. Cell death was analyzed by immunocytochemistry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and neuron-specific [2,2'-azino-bis(ethylbenzothiazoline-6-sulfonic acid)] assay. After 3 days of coculture in the absence of insult, PMNs caused massive neuron loss and dramatic morphological changes in glial cells (astrocyte detachment, aggregation). Furthermore PMNs exacerbated kainic acid- and oxygen glucose deprivation-induced neuron death by 20-30%. The cytotoxic effect of PMNs required heterocellular contact and were ameliorated by protease inhibitors. Lymphocytes, on the other hand, were not neurotoxic, but, instead, increased astrocyte proliferation. These findings suggest that PMN might represent a harmful part of inflammation after brain injury that can contribute to secondary damage.

    View details for DOI 10.1073/pnas.0303510101

    View details for Web of Science ID 000187937200061

    View details for PubMedID 14684829

  • Social experience alters the response to social stress in mice BRAIN BEHAVIOR AND IMMUNITY Avitsur, R., Stark, J. L., Dhabhar, F. S., Kramer, K. A., Sheridan, J. F. 2003; 17 (6): 426-437

    Abstract

    Individual differences in the response to stressful stimuli have been documented in humans and in a variety of animal species. Recently, we demonstrated that social stress induced a state of glucocorticoid (GC) resistance in mouse splenocytes, however this response was highly variable among cage mates. Since these studies were conducted using inbred mice (C57BL/6), it was suggested that environmental factors were the source of this variability. The following study examined possible factors that may have contributed to the development of individual differences in the susceptibility of mice to social stress. First, the effect of rearing conditions was studied by comparing the development of GC resistance in mice reared in isolation or in groups. In addition, the effect of previous social experiences was studied in mice that were re-housed to facilitate the formation of new social hierarchies in the cages. The results indicated that isolation altered the behavior of the mice during the social stress, but did not affect the development of GC resistance in response to the stress. Re-housing and the resulting loss of social status increased the susceptibility of mice to the development of GC resistance following social stress. Together, these findings indicate that environmental factors, such as previous social experiences, may alter the susceptibility to the effects of future social stress in inbred mice.

    View details for DOI 10.1016/S0889-1591(03)00034-5

    View details for Web of Science ID 000186412800004

    View details for PubMedID 14583234

  • Photoperiod affects the expression of sex and species differences in leukocyte number and leukocyte trafficking in congeneric hamsters PSYCHONEUROENDOCRINOLOGY Bilbo, S. D., Dhabhar, F. S., Viswanathan, K., Saul, A., Nelson, R. J. 2003; 28 (8): 1027-1043

    Abstract

    Sex differences in immune function are well documented. These sex differences may be modulated by social and environmental factors. Individuals of polygynous species generally exhibit more pronounced sex differences in immune parameters than individuals of monogamous species, often displaying an energetic trade-off between enhanced immunity and high mating success. During winter, animals contend with environmental conditions (e.g. low temperatures and decreased food availability) that evoke energetic-stress responses; many mammals restrict reproduction in response to photoperiod as part of an annual winter coping strategy. To test the hypothesis that extant sex and species differences in immune surveillance may be modulated by photoperiod, we examined leukocyte numbers in males and females of two closely related hamster species (Phodopus). As predicted, uniparental P. sungorus exhibited a robust sex difference, with total white blood cells, total lymphocytes, T cells, and B cells higher in females than males, during long days when reproduction occurs, but not during short days when reproduction usually stops. In contrast, biparental male and female P. campbelli exhibited comparable leukocyte numbers during both long and short days. To study sex differences in stress responses, we also examined immune cell trafficking in response to an acute (2 h) restraint stressor. During stressful challenges, it appears beneficial for immune cells to exit the blood and move to primary immune defense areas such as the skin, in preparation for potential injury or infection. Acute stress moved lymphocytes and monocytes out of the blood in all animals. Blood cortisol concentrations were increased in P. sungorus females compared to males at baseline (52%) and in response to restraint stress (38%), but only in long days. P. campbelli males and females exhibited comparable blood cortisol and stress responses during both long and short days. Our results suggest that interactions among social factors and the environment play a significant role in modulating sex and seasonal alterations in leukocyte numbers and stress responses.

    View details for DOI 10.1016/S0306-4530(02)00122-1

    View details for Web of Science ID 000186022200005

    View details for PubMedID 14529706

  • Expression of glucocorticoid resistance following social stress requires a second signal JOURNAL OF LEUKOCYTE BIOLOGY Avitsur, R., Padgett, D. A., Dhabhar, F. S., Stark, J. L., Kramer, K. A., Engler, H., Sheridan, J. F. 2003; 74 (4): 507-513

    Abstract

    Stimulation of splenocytes from socially stressed mice [social disruption (SDR)] with Gram-negative bacterial lipopolysaccharide (LPS) revealed a state of functional glucocorticoid (GC) resistance. LPS-stimulated splenocytes were less sensitive to the inhibitory effects of corticosterone. This study demonstrated that activation signals were required for the expression of splenic GC resistance. The results demonstrated that six cycles of SDR induced splenomegaly and increased the number of CD11b-positive monocytes. SDR also increased the viability of cultured, nonstimulated splenocytes, and addition of corticosterone reduced the viability of these cells in a dose-dependent manner. However, following stimulation with LPS, the sensitivity of SDR splenocytes to GC was reduced. Similar results were obtained using lipid A, a fraction of the LPS molecule that binds to Toll-like receptor (TLR)4. Furthermore, C3H/HeJ mice that do not possess a functional TLR4 molecule responded to SDR with an increased number of CD11b-positive monocytes in the spleen and increased viability of nonstimulated splenocytes. However, neither LPS nor lipid A stimulation resulted in the expression of GC resistance. Together, these findings suggest that the expression of GC resistance in response to SDR requires a second signal that can be provided by ligation of TLR4.

    View details for Web of Science ID 000187392300005

    View details for PubMedID 12960258

  • Enhanced cellular immune response in women with PTSD related to childhood abuse AMERICAN JOURNAL OF PSYCHIATRY Altemus, M., Cloitre, M., Dhabhar, F. S. 2003; 160 (9): 1705-1707

    Abstract

    Disturbed regulation of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathoadrenomedullary system in posttraumatic stress disorder (PTSD) suggests that immune function, which is modulated by these systems, also may be dysregulated in individuals with PTSD.Delayed-type hypersensitivity skin test responses were measured in 16 women with PTSD due to childhood sexual or physical abuse and 15 women who did not have a history of abuse, other trauma, or psychiatric disorders. HPA axis activity was assessed by examination of circadian salivary cortisol levels and a single time point measurement of plasma cortisol.Delayed-type hypersensitivity was enhanced in women with PTSD. Cortisol measures did not differ between PTSD and healthy comparison subjects.These results suggest that cell-mediated inflammatory reactions are greater in individuals with PTSD.

    View details for Web of Science ID 000185156400027

    View details for PubMedID 12944352

  • Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease BRAIN BEHAVIOR AND IMMUNITY Bosch, J. A., Berntson, G. G., Cacioppo, J. T., Dhabhar, F. S., Marucha, P. T. 2003; 17 (4): 251-259

    Abstract

    T lymphocytes and monocytes/macrophages are the most abundant cells found in the atherosclerotic plaque. These cells can migrate towards the activated endothelium through the local release of chemotactic cytokines, or chemokines. Given the important role of leukocyte migration in atherosclerosis and the role of stress in mediating leukocyte trafficking, the present study examined the effects of an acute stressor on the redistribution of T cells (CD3+) and monocytes that express the chemokine receptors CCR5, CCR6, CXCR1, CXCR2, CXCR3, and CXCR4. Forty-four undergraduate students underwent a public speaking task. The acute stressor induced sympathetic cardiac activation, parasympathetic cardiac withdrawal, lymphocytosis, and monocytosis (all p<.001). Although the total number of T lymphocytes did not change, there was a selective increase in the number of circulating T cells expressing CXCR2, CXCR3, and CCR5. The ligands of these receptors are chemokines known to be secreted by activated endothelial cells. Analyses of individual differences in stress-induced responses demonstrated a positive relationship between sympathetic cardiac reactivity and mobilization of the various T cell subsets (.35

    View details for DOI 10.1016/S0889-1591(03)00054-0

    View details for Web of Science ID 000183957300005

    View details for PubMedID 12831827

  • Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice JOURNAL OF NEUROIMMUNOLOGY Quan, N., Avitsur, R., Stark, J. L., He, L. L., Lai, W. M., Dhabhar, F., Sheridan, J. F. 2003; 137 (1-2): 51-58

    Abstract

    Splenocytes from socially stressed male mice display functional glucocorticoid (GC) resistance, viz., the antiproliferative effects of GC on lipopolysaccharide (LPS)-stimulated splenocytes is absent. In this study, we investigated changes in the structure and function of the glucocorticoid receptor (GR) in socially stressed animals. Changes of GR at both DNA and RNA levels were excluded. Reduced GR function was restricted to macrophages (CD11b(+)) in association with impaired nuclear translocation of GR after GC stimulation. Consequently, GC failed to block the activation of NF-kappa B in these cells. Thus, impaired nuclear translocation of GR and the lack of transcriptional suppression of NF-kappa B by GC were identified as the molecular mechanisms responsible for the observed GC resistance in spleens of socially stressed mice.

    View details for DOI 10.1016/S0165-5728(03)00042-0

    View details for Web of Science ID 000182443700006

    View details for PubMedID 12667647

  • Stress, leukocyte trafficking, and the augmentation of skin immune function NEUROENDOCRINE AND NEURAL REGULATION OF AUTOIMMUNE AND INFLAMMATORY DISEASE: MOLECULAR, SYSTEMS, AND CLINICAL INSIGHTS Dhabhar, F. S. 2003; 992: 205-217

    Abstract

    Delayed type hypersensitivity (DTH) reactions represent cell-mediated immune responses that exert important immunoprotective (resistance to viruses, bacteria, and fungi) or immunopathologic (allergic or autoimmune hypersensitivity) effects. We have used the skin DTH response as an in vivo model to study neuro-endocrine-immune interactions. We hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges (e.g., wounding) that may be imposed by a stressor (e.g., an aggressor). Studies showed that acute (2 hours) stress experienced before primary or secondary cutaneous antigen exposure induces significantly enhanced skin DTH. This enhancement involves innate as well as adaptive immune mechanisms. Adrenalectomy eliminates the stress-induced enhancement of DTH. Acute administration of physiological concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhances skin DTH. Compared with those in controls, DTH sites from acutely stressed or hormone-injected animals show significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene expression. In contrast to acute stress, chronic stress is immunosuppressive. Chronic exposure to corticosterone or acute exposure to dexamethasone significantly suppresses skin DTH. These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry. Elucidation of mechanisms mediating a stress-induced enhancement of skin immune function is important because such immunoenhancement can have protective (wound healing, resistance to infection) or pathological (allergic or autoimmune hypersensitivity) consequences.

    View details for Web of Science ID 000183697300020

    View details for PubMedID 12794060

  • Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo AMERICAN JOURNAL OF PATHOLOGY Fingerle-Rowson, G., Koch, P., Bikoff, R., Lin, X. C., Metz, C. N., Dhabhar, F. S., Meinhardt, A., Bucala, R. 2003; 162 (1): 47-56

    Abstract

    Glucocorticoid hormones are important anti-inflammatory agents because of their anti-inflammatory and proapoptotic action within the immune system. Their clinical usefulness remains limited however by side effects that result in part from their growth inhibitory action on sensitive target tissues. The protein mediator, macrophage migration inhibitory factor (MIF), is an important regulator of the host immune response and exhibits both glucocorticoid-antagonistic and growth-regulatory properties. MIF has been shown to contribute significantly to the development of immunopathology in several models of inflammatory disease. Although there is emerging evidence for a functional interaction between MIF and glucocorticoids in vitro, little is known about their reciprocal influence in vivo. We investigated the expression of MIF in rat tissues after ablation of the hypothalamic-pituitary-adrenal axis and after high-dose glucocorticoid administration. MIF expression is constitutive and independent of the influence of adrenal hormones. Hypophysectomy and the attendent loss of pituitary hormones, by contrast, decreased MIF protein content in the adrenal gland. Administration of dexamethasone was found to increase MIF protein expression in those organs that are considered to be sensitive to the growth inhibitory effects of glucocorticoids (immune and endocrine tissues, skin, and muscle). This increase was most likely because of a posttranscriptional regulatory effect because tissue MIF mRNA levels were not influenced by dexamethasone treatment. Finally, MIF immunoneutralization enhanced lymphocyte egress from blood during stress-induced lymphocyte redistribution, consistent with a functional interaction between MIF and glucocorticoids on immune cell trafficking in vivo. These findings suggest a role for MIF in both the homeostatic and physiological action of glucocorticoids in vivo.

    View details for Web of Science ID 000180009800007

    View details for PubMedID 12507889

  • Stress-induced augmentation of immune function - The role of stress hormones, leukocyte trafficking, and cytokines BRAIN BEHAVIOR AND IMMUNITY Dhabhar, F. S. 2002; 16 (6): 785-798

    Abstract

    Delayed-type hypersensitivity (DTH) reactions represent cell-mediated immune responses that exert important immunoprotective (resistance to viruses, bacteria, and fungi) or immunopathological (allergic or autoimmune hypersensitivity) effects. We initially utilized the skin DTH response as an experimental in vivo model to study neuro-endocrine-immune interactions in rodents. We hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges which may be imposed by a stressor. The skin DTH model allowed us to examine the effects of stress at the time of primary and secondary exposure to antigen. Studies showed that acute (2h) stress experienced before primary or secondary antigen exposure induces a significant enhancement of skin DTH. Importantly, this enhancement involved innate as well as adaptive immune mechanisms. Adrenalectomy eliminated the stress-induced enhancement of DTH. Acute administration of physiological (stress) concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhanced skin DTH. Compared with controls, DTH sites from acutely stressed or hormone-injected animals showed significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene expression. In contrast to acute stress, chronic stress was immunosuppressive. Chronic exposure to corticosterone, or acute exposure to dexamethasone significantly suppressed skin DTH. These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry. While these results are discussed from a mechanistic and clinical relevance perspective, it is acknowledged that much work remains to be done to elucidate the precise mechanisms mediating these bi-directional effects of stress and stress hormones and their clinical ramifications.

    View details for Web of Science ID 000180093200015

    View details for PubMedID 12480507

  • Social stress alters splenocyte phenotype and function JOURNAL OF NEUROIMMUNOLOGY Avitsur, R., Stark, J. L., Dhabhar, F. S., Sheridan, J. F. 2002; 132 (1-2): 66-71

    Abstract

    Social stress of group-housed male mice induced a state of functional glucocorticoid (GC) resistance in splenocytes. The following studies examined the effects of paired-fighting (PF) stress on immune cell distribution and function in spleens of male mice. Following six daily PF stress sessions, splenic monocytes and neutrophils increased and lymphocytes decreased. PF also altered the distribution of CD62L and CD11b positive monocytes. Additionally, PF augmented proliferation and lowered the sensitivity of LPS-stimulated splenocytes to the antiproliferative effects of corticosterone, suggesting that PF induced a state of GC resistance in splenocytes. Together, these findings indicate that social stress altered phenotype and function of splenic immune cells. These findings may have implications for the healing of bite wounds that are often associated with social stress in rodents.

    View details for Web of Science ID 000179542400009

    View details for PubMedID 12417435

  • Stress in adolescent females: Relationship to autoimmune diseases JOURNAL OF ADOLESCENT HEALTH McEwen, B. S., Dhabhar, F. 2002; 30 (4): 30-36

    View details for Web of Science ID 000174924300005

    View details for PubMedID 11943572

  • Short day lengths augment stress-induced leukocyte trafficking and stress-induced enhancement of skin immune function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bilbo, S. D., Dhabhar, F. S., Viswanathan, K., Saul, A., Yellon, S. M., Nelson, R. J. 2002; 99 (6): 4067-4072

    Abstract

    Environmental conditions influence the onset and severity of infection and disease. Stressful conditions during winter may weaken immune function and further compromise survival by means of hypothermia, starvation, or shock. To test the hypothesis that animals may use photoperiod to anticipate the onset of seasonal stressors and adjust immune function, we evaluated glucocorticoids and the distribution of blood leukocytes in Siberian hamsters (Phodopus sungorus) exposed to long day lengths (i.e., summer) or short day (SD) lengths (i.e., winter) at baseline and during acute stress. We also investigated the influence of photoperiod and acute stress on a delayed-type hypersensitivity response in the skin. SDs increased glucocorticoid concentrations and the absolute number of circulating blood leukocytes, lymphocytes, T cells, and natural killer cells at baseline in hamsters. During stressful challenges, it appears beneficial for immune cells to exit the blood and move to primary immune defense areas such as the skin, in preparation for potential injury or infection. Acute (2 h) restraint stress induced trafficking of lymphocytes and monocytes out of the blood. This trafficking occurred more rapidly in SDs compared to long days. Baseline delayed-type hypersensitivity responses were enhanced during SDs; this effect was augmented by acute stress and likely reflected more rapid redistribution of leukocytes out of the blood and into the skin. These results suggest that photoperiod may provide a useful cue by which stressors in the environment may be anticipated to adjust the repertoire of available immune cells and increase survival likelihood.

    View details for DOI 10.1073/pnas.062001899

    View details for Web of Science ID 000174511000125

    View details for PubMedID 11904451

  • Social disruption-induced glucocorticoid resistance: kinetics and site specificity JOURNAL OF NEUROIMMUNOLOGY Avitsur, R., Stark, J. L., Dhabhar, F. S., Padgett, D. A., Sheridan, J. F. 2002; 124 (1-2): 54-61

    Abstract

    Social disruption (SDR) of male mice has been shown to induce a state of functional glucocorticoid (GC) resistance in splenocytes. The present study demonstrated that GC resistance developed following repeated, but not acute exposure to SDR. GC resistance was long-lasting and persisted for at least 10 days after stress. In contrast, SDR did not alter cytokine secretion from peritoneal mononuclear cells treated with corticosterone. These findings suggest that SDR-induced GC resistance may be restricted to specific sites such as the spleen.

    View details for Web of Science ID 000174688600008

    View details for PubMedID 11958822

  • Stress-induced changes in skin barrier function in healthy women JOURNAL OF INVESTIGATIVE DERMATOLOGY Altemus, M., Rao, B., Dhabhar, F. S., Ding, W. H., Granstein, R. 2001; 117 (2): 309-317

    Abstract

    Despite clear exacerbation of several skin disorders by stress, the effect of psychologic or exertional stress on human skin has not been well studied. We investigated the effect of three different stressors, psychologic interview stress, sleep deprivation, and exercise, on several dermatologic measures: transepidermal water loss, recovery of skin barrier function after tape stripping, and stratum corneum water content (skin conductance). We simultaneously measured the effects of stress on plasma levels of several stress-response hormones and cytokines, natural killer cell activity, and absolute numbers of peripheral blood leukocytes. Twenty-five women participated in a laboratory psychologic interview stress, 11 women participated in one night of sleep deprivation, and 10 women participated in a 3 d exercise protocol. The interview stress caused a delay in the recovery of skin barrier function, as well as increases in plasma cortisol, norepinephrine, interleukin-1beta and interleukin-10, tumor necrosis factor-alpha, and an increase in circulating natural killer cell activity and natural killer cell number. Sleep deprivation also decreased skin barrier function recovery and increased plasma interleukin-1beta, tumor necrosis factor-alpha, and natural killer cell activity. The exercise stress did not affect skin barrier function recovery, but caused an increase in natural killer cell activity and circulating numbers of both cytolytic T lymphocytes and helper T cells. In addition, cytokine responses to the interview stress were inversely correlated with changes in barrier function recovery. These results suggest that acute psychosocial and sleep deprivation stress disrupts skin barrier function homeostasis in women, and that this disruption may be related to stress-induced changes in cytokine secretion.

    View details for Web of Science ID 000170668300019

    View details for PubMedID 11511309

  • Stress-induced enhancement of skin immune function: A role for gamma interferon PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Dhabhar, F. S., Satoskar, A. R., Bluethmann, H., David, J. R., McEwen, B. S. 2000; 97 (6): 2846-2851

    Abstract

    Contrary to the widespread belief that stress is necessarily immunosuppressive, recent studies have shown that, under certain conditions, stress can induce a significant enhancement of a skin cell-mediated immune response [delayed-type hypersensitivity (DTH) or contact hypersensitivity]. Adrenal stress hormones and a stress-induced trafficking of leukocytes from the blood to the skin have been identified as systemic mediators of this immunoenhancement. Because gamma interferon (IFNgamma) is an important cytokine mediator of DTH, the studies described here were designed to examine its role as a local mediator of the stress-induced enhancement of skin DTH. The effect of acute stress on skin DTH was examined in wild-type and IFNgamma receptor-deficient (IFNgammaR-/-) mice that had previously been sensitized with 2,4-dinitro-1-fluorobenzene. Acutely stressed wild-type mice showed a significantly larger DTH response than nonstressed mice. In contrast, IFNgammaR-/- mice failed to show a stress-induced enhancement of skin DTH. Immunoneutralization of IFNgamma in wild-type mice significantly reduced the stress-induced enhancement of skin DTH. In addition, an inflammatory response induced by direct IFNgamma administration to the skin was significantly enhanced by acute stress. Our results suggest that IFNgamma is an important local mediator of a stress-induced enhancement of skin DTH. These studies are clinically relevant because, depending on the nature of the antigen, DTH reactions mediate numerous protective (e.g., resistance to viral, bacterial, parasitic, and fungal infections) or pathological (e.g., autoimmune reactions and contact sensitivity reactions such as that to poison ivy) immune responses.

    View details for Web of Science ID 000085941400080

    View details for PubMedID 10706626

  • Enhancing versus suppressive effects of stress hormones on skin immune function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Dhabhar, F. S., McEwen, B. S. 1999; 96 (3): 1059-1064

    Abstract

    Delayed-type hypersensitivity (DTH) reactions are antigen-specific cell-mediated immune responses that, depending on the antigen, mediate beneficial (e.g., resistance to viruses, bacteria, and fungi) or harmful (e.g., allergic dermatitis and autoimmunity) aspects of immune function. Contrary to the idea that stress suppresses immunity, we have reported that short-duration stressors significantly enhance skin DTH and that a stress-induced trafficking of leukocytes to the skin may mediate this immunoenhancement. Here, we identify the hormonal mediators of a stress-induced enhancement of skin immunity. Adrenalectomy, which eliminates the glucocorticoid and epinephrine stress response, eliminated the stress-induced enhancement of skin DTH. Low-dose corticosterone or epinephrine administration significantly enhanced skin DTH and produced a significant increase in the number of T cells in lymph nodes draining the site of the DTH reaction. In contrast, high-dose corticosterone, chronic corticosterone, or low-dose dexamethasone administration significantly suppressed skin DTH. These results suggest a role for adrenal stress hormones as endogenous immunoenhancing agents. These results also show that hormones released during an acute stress response may help prepare the immune system for potential challenges (e.g., wounding or infection) for which stress perception by the brain may serve as an early warning signal.

    View details for Web of Science ID 000078484100048

    View details for PubMedID 9927693

  • Neuroendocrine-related effects of long-term, 'binge' cocaine administration: Diminished individual differences in stress-induced corticosterone response NEUROENDOCRINOLOGY Sarnyai, Z., Dhabhar, F. S., McEwen, B. S., Kreek, M. J. 1998; 68 (5): 334-344

    Abstract

    Acute cocaine administration activates behavioral and neuroendocrine processes associated with the stress response. However, much less is known about the effects of chronic, long-term cocaine administration on neuroendocrine adaptations and individual vulnerability to stress. We hypothesized that chronic 'binge' cocaine administration may serve as a chronic pharmacological stressor leading to a hyperactivity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and alterations in its feedback mechanisms. In order to test this hypothesis, the effects of long-term (3 and 6 weeks) 'binge' pattern cocaine administration (3x15 mg/kg cocaine, i.p., daily, during the early phase of the light cycle) on body weight, adrenal gland weight, basal and stress-induced activity of the corticosterone (CORT) and basal plasma testosterone (T) levels were measured. Both 3 and 6 weeks 'binge' cocaine administration decreased body weight gain, increased the weight of adrenal glands and increased basal CORT levels. Plasma T levels were suppressed by both 3 and 6 weeks of cocaine treatment. No correlation was found between elevated CORT and low T levels at any time point. Neither chronic saline nor cocaine administration altered stress-induced CORT secretion. CORT levels 60 min following the restraint stress (recovery) were significantly lower than pre-stress basal levels after 3 and 6 weeks of cocaine, but not saline, administration. Moreover, initial individual differences in stress-induced CORT response, i.e. low and high responsivity to restraint prior to any saline or cocaine injections, were maintained in control rats but became diminished in cocaine-treated rats. These results indicate that chronic binge cocaine administration leads to sustained activation of the HPA axis and alters processes underlying individual vulnerability to stress.

    View details for Web of Science ID 000077274500006

    View details for PubMedID 9822801

  • MIF expression in the rat brain: Implications for neuronal function MOLECULAR MEDICINE Bacher, M., Meinhardt, A., Lan, H. Y., Dhabhar, F. S., Mu, W., Metz, C. N., Chesney, J. A., GEMSA, D., Donnelly, T., Atkins, R. C., Bucala, R. 1998; 4 (4): 217-230

    Abstract

    The mediator known historically as macrophage migration inhibitory factor (MIF) has been identified recently as being released into the circulation by the anterior pituitary gland as a consequence of stress or during a systemic inflammatory response. Macrophages and T cells also secrete MIF, both in response to proinflammatory factors or upon stimulation with glucocorticoids. Once released, MIF "overrides" or counterregulates the immunosuppressive effects of steroids on cytokine production and immune cellular activation. To further investigate the biology of MIF and its role in the neuroendocrine system, we have studied the regional and cellular expression of MIF in brain tissue obtained from normal rats and rats administered LPS intracisternally.Rat brain sections were analyzed by immunohistochemistry utilizing an affinity-purified, anti-MIF antibody raised to recombinant MIF, and by in situ hybridization using a digoxigenin-labeled, antisense MIF cRNA probe. The kinetics of MIF mRNA expression in brain were compared with that of IL-1, IL-6, and TNF-alpha by RT-PCR of total brain RNA. The cerebrospinal fluid content of MIF and TNF-alpha proteins was analyzed by Western blotting and ELISA.A strong baseline expression pattern for MIF was observed in neurons of the cortex, hypothalamus, hippocampus, cerebellum, and pons. By in situ hybridization, MIF mRNA was found predominantly in cell bodies whereas MIF protein was detected mostly within the terminal fields associated with neurons. There was a marked pattern of MIF immunoreactivity within the mossy fibers of the dentate gyrus and dendrites of the hippocampal CA3 field. These structures have been shown previously to be involved in glucocorticoid-induced tissue damage within the hippocampus, suggesting an association between MIF and targets of glucocorticoid action. The intracisternal injection of LPS increased MIF mRNA and protein expression in brain and MIF immunoreactivity was due in part to infiltrating monocytes/macrophages. MIF protein also was found to be rapidly released into the cerebrospinal fluid. This response corresponded with that of LPS-induced cytokine release and MIF mRNA expression increased in a distribution that colocalized in large part with that of TNF-alpha, IL-1 beta, and IL-6.The significant levels of baseline and inducible MIF expression in the brain and its regional association with glucocorticoid action underscore the importance of this mediator as a physiological regulator of the inflammatory stress response and further define its role within the neuroendocrine system.

    View details for Web of Science ID 000073740200003

    View details for PubMedID 9606175

  • Stress-induced enhancement of cell-mediated immunity NEUROIMMUNOMODULATION Dhabhar, F. S. 1998; 840: 359-372

    Abstract

    We have demonstrated that acute stress induces a large-magnitude, rapid, and reversible redistribution of leukocytes from the blood to other compartments within the body. These changes in leukocyte distribution are mediated by adrenal stress hormones. Because the skin is one of the target organs of a stress-induced redistribution of leukocyes, we hypothesized that such a leukocyte redistribution could be one of the factors by which acute stress may enhance cutaneous immune function. This hypothesis was tested by examining the effects of acute stress on cutaneous delayed-type hypersensitivity (DTH). DTH reactions are antigen-specific, cell-mediated immune responses that, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, and fungi) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. DTH was induced by challenging the pinnae of previously sensitized rats with 2,4-dinitro-1-fluorobenzene (DNFB). Experiments showed that acute stress administered immediately before the introduction of an antigenic challenge significantly enhances a cutaneous DTH response. In contrast, chronic stress suppresses cutaneous DTH. These results demonstrate a bidirectional relationship between stress and immune function, such that acute stress enhances, while chronic stress suppresses, an important class of immune responses in vivo. They also suggest that stress-induced alterations in lymphocyte redeployment within the body may play an important role in mediating these bidirectional effects of stress on cell-mediated immunity.

    View details for Web of Science ID 000074444500033

    View details for PubMedID 9629263

  • Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: A potential role for leukocyte trafficking BRAIN BEHAVIOR AND IMMUNITY Dhabhar, F. S., McEwen, B. S. 1997; 11 (4): 286-306

    Abstract

    Delayed type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses which, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, fungi, and certain tumors) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. We have shown that acute stress administered immediately before antigenic challenge results in a significant enhancement of a skin DTH response in rats. A stress-induced trafficking or redeployment of leukocytes to the skin may be one of the factors mediating this immunoenhancement. Here we investigate the effects of varying the duration, intensity, and chronicity of stress on the DTH response and on changes in blood leukocyte distribution and glucocorticoid levels. Acute stress administered for 2 h prior to antigenic challenge, significantly enhanced the DTH response. Increasing the duration of stress from 2 h to 5 h produced the same magnitude enhancement in cutaneous DTH. Moreover, increasing the intensity of acute stress produced a significantly larger enhancement of the DTH response which was accompanied by increasing magnitudes of leukocyte redeployment. In contrast, chronic stress suppressed the DTH response when it was administered for 3 weeks before sensitization and either discontinued upon sensitization, or continued an additional week until challenge, or extended for one week after challenge. The stress-induced redeployment of peripheral blood lymphocytes was attenuated with increasing exposure to chronic stress and correlated with attenuated glucocorticoid responsivity. These results suggest that stress-induced alterations in lymphocyte redeployment may play an important role in mediating the bi-directional effects of acute versus chronic stress on cell-mediated immunity in vivo.

    View details for Web of Science ID 000072322300005

    View details for PubMedID 9512816

  • Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress NEUROSCIENCE Galea, L. A., McEwen, B. S., Tanapat, P., Deak, T., Spencer, R. L., Dhabhar, F. S. 1997; 81 (3): 689-697

    Abstract

    The present study investigated the effects of 21 days of chronic restraint stress on neural and endocrine parameters in male and female rats. Consistent with previous results, repeated restraint stress induced apical dendritic atrophy (a decrease in the number of apical branch points and dendritic length) of the CA3c pyramidal neurons in male rats. In contrast, female rats did not show significant dendritic atrophy in the apical field in response to repeated restraint stress. Female rats did show a decrease in the number of branch points in the basal dendritic tree compared to male rats in response to repeated restraint stress. Baseline and stress levels of plasma corticosterone were higher in female rats compared to male rats. Females exhibited slightly longer increases in corticosterone levels throughout the 21 days of restraint stress than males, indicating that the male corticosterone response to stress exhibited greater habituation. Plasma corticosteroid-binding globulin levels of female rats were also higher than those of male rats throughout the experiment. There was no change in plasma corticosteroid-binding globulin levels in male rats during the restraint stress, while there was a decrease in plasma corticosteroid-binding globulin levels in female rats during the restraint stress. Plasma estradiol levels in female rats also decreased in response to the chronic stress. In view of the qualitatively different dendritic atrophy found in males and females in appears unlikely that sex differences in the corticosteroid-binding globulin and corticosterone response can account for these morphological differences.

    View details for Web of Science ID A1997XX98200009

    View details for PubMedID 9316021

  • Effects of viral infection on corticosterone secretion and glucocorticoid receptor binding in immune tissues PSYCHONEUROENDOCRINOLOGY Miller, A. H., Spencer, R. L., Pearce, B. D., Pisell, T. L., Tanapat, P., LEUNG, J. J., Dhabhar, F. S., McEwen, B. S., Biron, C. A. 1997; 22 (6): 455-474

    Abstract

    During an immune challenge it has been suggested that responding cells secrete cytokines which then stimulate the release of glucocorticoids. Glucocorticoids, in turn, are believed to bind to their receptors in target immune tissues and provide feedback inhibition on evolving immune responses. The foundations for this hypothesis have been drawn primarily from studies on animal models of autoimmune and/or inflammatory processes, and the relevance of these glucocorticoid-immune interactions to viral infections has not been extensively examined. Accordingly, we infected mice with lymphocytic choriomeningitis virus (LCMV) and measured plasma corticosterone and cytosolic glucocorticoid receptor (GR) binding at multiple time points throughout the day and throughout infection (days 3, 5, 7 and 10 post infection). Despite a vigorous immune response to this virus, LCMV infection was associated with minimal and transient increases in corticosterone secretion. Interestingly, however, significant decreases in cytosolic GR were found in immune tissues. Receptor decreases were characterized by a significant decrease in GR binding during the diurnal rise in corticosterone in the spleen and thymus of infected but not uninfected animals on days 5-10 post infection. In addition, in the morning on these days, GR binding in the spleen of infected mice was decreased compared to uninfected control mice. Following an acute injection of corticosterone on day 7 post infection, LCMV-infected animals exhibited a significantly greater decrease in splenic GR binding than uninfected control mice, suggesting an increased sensitivity to corticosterone in infected animals. No changes were found in the affinity (Kd) of the GR during infection, nor was there evidence of an infection-associated decrease in plasma corticosteroid binding globulin. The appearance of significant GR changes in the spleen and thymus, in the absence of significant elevations in corticosterone or decreases in its binding protein, suggests that cytokines and/or other factors produced within the immune tissues during infection either directly influenced GR number and/or function or influenced the local availability of corticosterone. Taken together, the results indicate that interactions between the neuroendocrine and immune systems can be modified at the level of the GR in the context of an ongoing immune response such as during a viral infection.

    View details for Web of Science ID A1997XW96200006

  • Adaptation to prolonged or repeated stress - Comparison between rat strains showing intrinsic differences in reactivity to acute stress NEUROENDOCRINOLOGY Dhabhar, F. S., McEwen, B. S., Spencer, R. L. 1997; 65 (5): 360-368

    Abstract

    Sprague-Dawley (SD), Fischer 344 (F344) and Lewis (LEW) rats are used in a wide variety of laboratory studies. Compared to SD and LEW rats, F344 rats show significantly greater activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to acute stress, or to immunologic challenge. These differences in HPA axis responsivity have been the basis for numerous studies investigating strain differences in immunological and behavioral parameters. However, strain differences in the adaptation of the HPA axis response to prolonged stress, or to repeated stress, have not been investigated. This series of studies demonstrates that F344 rats maintain significantly higher ACTH and corticosterone levels than SD and LEW rats during a single prolonged stress session. Furthermore, F344 rats show virtually no habituation or adaptation of the corticosterone stress response during a single prolonged (4 h) stress session, or during stress sessions repeated over a period of 10 days. In contrast, SD and LEW rats show habituation both within and across stress sessions. Strain differences in HPA axis responsivity are also reflected in the significant adrenal hypertrophy observed in F344 rats (but not in SD or LEW rats) following repeated stress. These results show that strain differences in HPA axis responsivity, which are observed under conditions of acute stress, are further amplified during prolonged or repeated stress. These differences under prolonged or repeated stress conditions may consequently magnify the behavioral and immunological differences observed between strains under basal as well as challenged conditions.

    View details for Web of Science ID A1997WY14400007

    View details for PubMedID 9158068

  • Long-term corticosteroid treatment but not chronic stress affects 11 beta-hydroxysteroid dehydrogenase type I activity in rat brain and peripheral tissues JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY Jellinck, P. H., Dhabhar, F. S., Sakai, R. R., McEwen, B. S. 1997; 60 (5-6): 319-323

    Abstract

    Long-term treatment (21 days) of male rats with corticosterone in the drinking water caused a significant increase in the activity of the NADP-dependent form of 11beta-hydroxysteroid dehydrogenase (11-HSD1) in the pituitary, thymus, and spleen, (marginally in the hippocampus, amygdala and lymph nodes), without having any effect in a number of other central and peripheral tissues. In contrast, repeated restraint stress, although increasing plasma corticosterone to the same level as that observed after its administration, failed to change the activity of this key regulatory enzyme, which allows aldosterone to exert its specific effects in the presence of a large excess of corticosterone. This resistance to elevation in 11-HSD activity was also observed in the thymuses of subordinate rats during social stratification in a visible burrow system. In both cases, the circulating levels of corticosterone were much higher in stressed rats than in control animals. Factors which might account for these differences in response are discussed and compared with the situation in intact cells where, unlike in tissue homogenates, the reduction of 11-dehydrocorticosterone to corticosterone (reductase activity) appears to predominate.

    View details for Web of Science ID A1997XJ84900008

    View details for PubMedID 9219923

  • The role of adrenocorticoids as modulators of immune function in health and disease: Neural, endocrine and immune interactions BRAIN RESEARCH REVIEWS McEwen, B. S., Biron, C. A., Brunson, K. W., Bulloch, K., Chambers, W. H., Dhabhar, F. S., GOLDFARB, R. H., Kitson, R. P., Miller, A. H., Spencer, R. L., Weiss, J. M. 1997; 23 (1-2): 79-133

    View details for Web of Science ID A1997WN18500005

    View details for PubMedID 9063588

  • Stress-induced changes in blood leukocyte distribution - Role of adrenal steroid hormones JOURNAL OF IMMUNOLOGY Dhabhar, F. S., Miller, A. H., McEwen, B. S., Spencer, R. L. 1996; 157 (4): 1638-1644

    Abstract

    The numbers and proportions of leukocytes in the blood provide an important representation of the state of activation of the immune system, and of the pattern of distribution of immune cells in the body. We have shown previously that acute stress induces large, rapid, and reversible changes in the distribution of peripheral blood leukocyte subpopulations in the rat. The studies described here specifically investigate the role played by adrenal steroid hormones in mediating stress-induced changes in blood leukocyte distribution. Since adrenal steroids act at two distinct receptor subtypes that show a heterogeneity of expression in immune cells and tissues, the role played by each subtype in mediating changes in leukocyte distribution is also investigated. Cyanoketone, a corticosterone (CORT) synthesis inhibitor, significantly reduced the decrease in lymphocyte numbers observed during stress and significantly enhanced the increase in neutrophil numbers observed after the cessation of stress. Acute administration of aldosterone (a specific type I adrenal steroid receptor agonist) to adrenalectomized animals did not have a significant effect on blood leukocyte numbers. In contrast, acute administration of CORT (the endogenous type I and type II receptor agonist), or RU28362 (a specific type II receptor agonist), to adrenalectomized animals produced changes in leukocyte distribution that were similar to those observed in intact animals during stress. These results suggest that CORT, acting at the type II adrenal steroid receptor, is a major mediator of the stress-induced changes in blood lymphocyte and monocyte distribution.

    View details for Web of Science ID A1996VH12400041

    View details for PubMedID 8759750

  • Stress-induced enhancement of antigen-specific cell-mediated immunity JOURNAL OF IMMUNOLOGY Dhabhar, F. S., McEwen, B. S. 1996; 156 (7): 2608-2615

    Abstract

    The studies described here demonstrate that the activation of the physiologic stress response systems of the body can enhance immune function in vivo. This enhancement is observed as a large and long lasting increase in allergic contact sensitivity or delayed-type hypersensitivity, an immune reaction which involves an Ag-specific, cell-mediated immune response. In contrast, acute stress has no effect on the course of irritant contact sensitivity, an immune reaction that does not involve an Ag-specific memory response. A comparison of infiltrating leukocyte numbers in sections of inflamed skin from unstressed and stressed animals shows that stress induces a significant and persistent increase in numbers of leukocytes at the site of the delayed-type hypersensitivity reaction. These results demonstrate that a relatively mild behavioral manipulation can enhance an important class of immune responses that mediate harmful (allergic dermatitis) as well as beneficial (resistance to certain viruses, bacteria, and tumors) aspects of immune function. The implications that these studies have for clinical, diagnostic, and experimental manipulations involving cell-mediated immune function are discussed.

    View details for Web of Science ID A1996UB15500040

    View details for PubMedID 8786326

  • EFFECTS OF STRESS ON IMMUNE CELL DISTRIBUTION - DYNAMICS AND HORMONAL MECHANISMS JOURNAL OF IMMUNOLOGY Dhabhar, F. S., Miller, A. H., McEwen, B. S., Spencer, R. L. 1995; 154 (10): 5511-5527

    Abstract

    Immune cell trafficking is crucial to the performance of the surveillance as well as effector functions of the immune system. Because immune cells travel between tissues through the bloodstream, the numbers and proportions of leukocytes in the circulation provide an important representation of the state of leukocyte distribution in the body. The studies described here examine significant and selective changes in numbers and percentages of peripheral blood leukocyte subpopulations in the rat. These changes were rapidly induced under conditions of mild acute stress. Stress-induced increases in plasma corticosterone were accompanied by a significant decrease in numbers and percentages of lymphocytes, and by an increase in numbers and percentages of neutrophils. flow cytometric analysis revealed that B cell, NK cell, and monocyte numbers showed a greater stress-induced decrease than did T cells. All stress-induced changes were observed during the light (inactive) as well as the dark (active) period of the animal's diurnal cycle. Importantly, the stress-induced changes in leukocyte numbers and percentages were rapidly reversed upon the cessation of stress. Furthermore, the effects of stress were largely dependent on adrenal hormones, because the magnitude of the stress-induced changes was significantly reduced in adrenalectomized animals. Moreover, administration of corticosterone to adrenalectomized animals resulted in a close replication of stress-induced changes observed in adrenal-intact animals. These results suggest that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments. Such a redistribution may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge.

    View details for Web of Science ID A1995QW90100066

    View details for PubMedID 7730652

  • DIFFERENTIAL ACTIVATION OF ADRENAL-STEROID RECEPTORS IN NEURAL AND IMMUNE TISSUES OF SPRAGUE-DAWLEY, FISCHER-344, AND LEWIS RATS JOURNAL OF NEUROIMMUNOLOGY Dhabhar, F. S., Miller, A. H., McEwen, B. S., Spencer, R. L. 1995; 56 (1): 77-90

    Abstract

    Sprague Dawley (SD), Fischer 344 (F344), and Lewis (LEW) rats are used in a wide variety of laboratory studies. Compared to SD and LEW rats, F344 rats show significantly greater corticosterone secretion in response to stress, or to immune challenge. These strain differences in hypothalamic-pituitary-adrenal (HPA) axis responsivity have been the basis for many comparative studies investigating immunological and behavioural differences between the three strains. However, the effects of these strain differences in HPA axis responsivity have not been investigated at the level of adrenal steroid receptor activation in target tissues. The present study demonstrates that compared to SD and LEW rats, F344 rats exhibited a greater magnitude of Type II adrenal steroid receptor activation in brain tissues during stress. In contrast, Type II receptor activation in immune tissues of F344 rats following stress was similar to that of SD rats. Importantly, LEW rats exhibited the lowest magnitude of activation of Type II receptors in immune tissues during stress. No differences were observed between strains in the extent of stress-induced Type I adrenal steroid receptor activation. The observed differences between strains in corticosteroid-binding globulin (CBG) levels in plasma, pituitary, and immune tissue may mediate the differential access of corticosterone to neural versus immune tissues. These results indicate that strain differences in corticosterone secretion are manifested by differences in Type II receptor activation in neural as well as immune tissues. Moreover, they suggest that increased access of corticosterone to adrenal steroid receptors in brain areas of F344 rats may contribute to behavioural differences between strains, whereas decreased access of hormone to receptors in immune tissues of LEW rats may contribute to strain differences in susceptibility to autoimmune disease.

    View details for Web of Science ID A1995QB84000009

    View details for PubMedID 7822484

  • EFFECTS OF SELECTIVE TYPE-I AND TYPE-II ADRENAL-STEROID AGONISTS ON IMMUNE CELL DISTRIBUTION ENDOCRINOLOGY Miller, A. H., Spencer, R. L., Hassett, J., Kim, C., Rhee, R., CIUREA, D., Dhabhar, F., McEwen, B., Stein, M. 1994; 135 (5): 1934-1944

    Abstract

    Adrenal steroids exert their effects through two distinct adrenal steroid receptor subtypes; the high affinity type I, or mineralocorticoid, receptor and the lower affinity type II, or glucocorticoid, receptor. Adrenal steroids have well known effects on immune cell distribution, and although both type I and II receptors are expressed in immune cells and tissues, few data exist on the relative effects mediated through these two receptor subtypes. Accordingly, we administered selective type I and II adrenal steroid receptor agonists to young adult male Sprague-Dawley rats for 7 days and then measured immune cell distribution in the peripheral blood and spleen. Results were compared with those of similar studies using the naturally occurring glucocorticoid of the rat, corticosterone, which binds both type I and II receptors. The majority of the well characterized effects of adrenal steroids on peripheral blood immune cells (increased neutrophils and decreased lymphocytes and monocytes) were reproduced by the type II receptor agonist, RU28362. RU28362 decreased the numbers of all lymphocyte subsets [T-cells, B-cells, and natural killer (NK) cells] to very low absolute levels. The largest relative decrease (i.e. in percentage) was seen in B-cells, whereas NK cells exhibited the least relative decrease and actually showed a 2-fold increase in relative percentage during RU28362 treatment. Similar to RU28362, the type I receptor agonist, aldosterone, significantly reduced the number of lymphocytes and monocytes. In contrast to RU28362, however, aldosterone significantly decreased the number of neutrophils. Moreover, aldosterone decreased the number of T-helper cells and NK cells, while having no effect on the number of B-cells or T-suppressor/cytotoxic cells. Corticosterone at physiologically relevant concentrations had potent effects on immune cell distribution, which were indistinguishable from those of the type II receptor agonist, RU28362. Taken together, these results indicate that effects of adrenal steroids on immune cell distribution are dependent on the receptor subtype involved as well as the specific cell type targeted. These factors allow for varied and complex effects of adrenal steroids on the immune system under physiological conditions.

    View details for Web of Science ID A1994PR66700029

    View details for PubMedID 7956914

  • DIURNAL AND ACUTE STRESS-INDUCED CHANGES IN DISTRIBUTION OF PERIPHERAL-BLOOD LEUKOCYTE SUBPOPULATIONS BRAIN BEHAVIOR AND IMMUNITY Dhabhar, F. S., Miller, A. H., Stein, M., McEwen, B. S., Spencer, R. L. 1994; 8 (1): 66-79

    Abstract

    In this study, we examined hormonal regulation of the distribution profiles of leukocyte subpopulations in the peripheral blood of rats. Flow cytometric analysis revealed significant and selective changes in the numbers and the percentages of peripheral blood leukocyte subpopulations which were a function of diurnal variations in hormone secretion and hormonal changes induced by acute stress. Changes in numbers and percentages of leukocyte subpopulations, which varied with time of day, were similar to changes observed under stress conditions. At the beginning of the rat's active period, and after 1 h of restraint stress, there was a significant reduction in numbers of leukocytes and lymphocytes. This reduction was primarily accounted for by a decrease in numbers of B cells, natural killer cells, monocytes (diurnal study), and helper T cells (diurnal study). There was also a significant decrease in the percentage of lymphocytes which was mirrored by an increase in the percentage of neutrophils in the peripheral blood. Peripheral blood leukocyte numbers were inversely related to plasma corticosterone levels. These results suggest that the endocrine system plays a role in the regulation of immune cell turnover and/or redistribution between immune compartments under conditions of normal daily experiences, namely, the diurnal cycle, and mild acute stress. They also suggest that these effects are selective for certain subpopulations of leukocytes.

    View details for Web of Science ID A1994NA42600006

    View details for PubMedID 8003772

  • STRESS-RESPONSE, ADRENAL-STEROID RECEPTOR LEVELS AND CORTICOSTEROID-BINDING GLOBULIN LEVELS - A COMPARISON BETWEEN SPRAGUE-DAWLEY, FISCHER-344 AND LEWIS RATS BRAIN RESEARCH Dhabhar, F. S., McEwen, B. S., Spencer, R. L. 1993; 616 (1-2): 89-98

    Abstract

    Histocompatible Fischer 344 (F344) and Lewis (LEW) rats provide a comparative model for investigating the interactions between the nervous, endocrine and immune systems. The outbred Sprague-Dawley (SD) is the maternal strain for the inbred F344 and LEW strains. In this study we report large differences in the diurnal and stress corticosterone (CORT) profiles of these three genetically related strains: (1) F344 rats had significantly higher diurnal and stress CORT levels than SD and LEW rats; (2) in the morning, stress CORT levels of SD and F344 rats returned towards basal 1 h after cessation of the stressor, whereas stress CORT levels of LEW rats had not returned to basal by this time; and (3) in the evening, SD and F344 rats showed the expected evening rise in basal CORT levels, whereas LEW rats failed to show this rise. In light of the large differences in CORT levels, we expected to observe strain differences in absolute levels of Type I (mineralocorticoid) and Type II (glucocorticoid) adrenal steroid receptors in neural as well as immune tissue. However, we found no significant strain differences in levels of Type I receptors in the hippocampus, hypothalamus, pituitary, thymus, spleen and peripheral blood mononuclear cells. Similarly, we saw no significant strain differences in levels of Type II receptors in most of the tissues surveyed, with the notable exception that LEW rats showed higher Type II binding in the thymus, and SD rats showed small, but significantly higher Type II binding in the hippocampus. We also studied strain differences in levels of corticosteroid-binding globulin (CBG). F344 rats expressed significantly higher CBG levels than SD and LEW rats, in plasma, spleen and thymus. Future studies will investigate whether the substantial differences between strains in levels of CORT and CBG, in the context of few strain differences in post-adrenalectomy adrenal steroid receptor levels in neural and immune tissue, translate into differences in receptor occupancy/activation under resting conditions, or following stress.

    View details for Web of Science ID A1993LL21900013

    View details for PubMedID 8395308

Conference Proceedings


  • A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function Dhabhar, F. S. OXFORD UNIV PRESS INC. 2009: 215-236

    Abstract

    Stress is known to suppress or dysregulate immune function and increase susceptibility to disease. Paradoxically, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that galvanizes the neuroendocrine, cardiovascular, and musculoskeletal systems into action to enable survival. Therefore, it is unlikely that short-term stress would suppress immune function at a time when it may be critically required for survival (e.g., in response to wounding and infection by a predator or aggressor). In fact, studies have shown that stress can enhance immune function under certain conditions. Several factors influence the direction (enhancing versus suppressive) of the effects of stress on immune function: (1) Duration: acute or short-term stress experienced at the time of activation of an immune response enhances innate and adaptive immune responses. Chronic or long-term stress can suppress or dysregulate immune function. (2) Leukocyte distribution: compartments (e.g., skin), that are enriched with immune cells during acute stress show immuno-enhancement, while those that are depleted of leukocytes (e.g., blood), show immuno-suppression. (3) The differential effects of physiologic versus pharmacologic stress hormones: Endogenous hormones in physiological concentrations can have immuno-enhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immuno-suppressive. (4) Timing: immuno-enhancement is observed when acute stress is experienced during the early stages of an immune response while immuno-suppression may be observed at late stages. The type of immune response (protective, regulatory/inhibitory, or pathological) that is affected determines whether the effects of stress are ultimately beneficial or harmful for the organism. Arguments based on conservation of energy have been invoked to explain potential adaptive benefits of stress-induced immuno-suppression, but generally do not hold true because most mechanisms for immuno-suppression expend, rather than conserve, energy. We propose that it is important to study, and if possible, to clinically harness, the immuno-enhancing effects of the acute stress response that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve.

    View details for DOI 10.1093/icb/icp045

    View details for Web of Science ID 000269962300003

    View details for PubMedID 21665815

  • A hassle a day may keep the doctor away: Stress and the augmentation of immune function Dhabhar, F. S. OXFORD UNIV PRESS INC. 2002: 556-564

    Abstract

    Stress may be defined as a sequence of events, that begins with a stimulus (stressor), that is recognized by the brain (stress perception), and which results in the activation of physiologic fight/flight/fright systems within the body (stress response). Many evolutionary selection pressures are stressors, and one of the primary functions of the brain is to perceive stress, warn the body of danger, and enable an organism to respond. We hypothesized that under acute conditions, just as the stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges (e.g., wounding) which may be imposed by a stressor (e.g., an aggressor). Initial studies showed that acute (2h) stress induced a significant trafficking of immune cells to the skin. Since the skin is an organism's major protective barrier, we hypothesized that this leukocyte redistribution may serve to enhance skin immunity during acute stress. We tested this hypothesis using the delayed type hypersensitivity (DTH) reaction, which mediates resistance to various infectious agents, as a model for skin immune function. Acute stress administered immediately before antigen exposure significantly enhanced skin DTH. Adrenalectomy (ADX) eliminated the stress-induced enhancement of DTH while administration of physiological doses of corticosterone and/or epinephrine to ADX animals enhanced skin DTH in the absence of stress. These studies showed that changes in leukocyte distribution and circulating stress hormones are systemic mediators of the immunoenhancing effects of acute stress. We recently identified gamma interferon as a local cytokine mediator of a stress-induced immunoenhancement. Our results suggest that during acute stress the brain sends preparatory warning signals to the immune system just as it does to other fight/flight systems of the body.

    View details for Web of Science ID 000179058900017

    View details for PubMedID 21708751

  • Acute stress enhances while chronic stress suppresses skin immunity - The role of stress hormones and leukocyte trafficking Dhabhar, F. S. NEW YORK ACAD SCIENCES. 2000: 876-893

    Abstract

    Delayed-type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses that, depending on the antigen, mediate beneficial (resistance to viruses, bacteria, fungi) or harmful (allergic dermatitis, autoimmunity) aspects of immunity. Contrary to the widely held notion that stress is immunosuppressive, we have shown that under certain conditions, stress can enhance immune function. DTH reactions can be studied in rats or mice by challenging the pinnae of previously sensitized animals with antigen. Studies have shown that acute stress administered immediately before antigen exposure significantly enhances skin DTH. In contrast, chronic stress significantly suppresses skin DTH. Stress-induced changes in leukocyte distribution may contribute to these bidirectional effects of stress, since acute stress induces a significant mobilization of leukocytes from the blood to the skin, whereas chronic stress suppresses leukocyte mobilization. In order to identify the hormonal mediators of the observed effects of stress, we first showed that adrenalectomy (ADX) eliminates the stress-induced enhancement of DTH. Acute administration (to ADX animals) of low doses of corticosterone and/or epinephrine significantly enhances skin DTH. In contrast, acute administration of high doses of corticosterone, low doses of dexamethasone, or chronic administration of moderate doses of corticosterone, suppress skin DTH. Thus, the timing and duration of stress may significantly affect the nature (enhancing versus suppressive) of the effects of stress on skin immune function. These results suggest that during acute stress, stress hormones may help enhance immune function by informing the immune system about impending challenges (e.g., wounding or infection) that may be imposed by a stressor (e.g., an aggressor). Thus, during acute stress, the brain may send a warning signal to the immune system, just as it does to other fight/flight systems in the body.

    View details for Web of Science ID 000171939400088

    View details for PubMedID 11268419

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