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  • OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis. Proceedings of the National Academy of Sciences of the United States of America Gwyer Findlay, E., Danks, L., Madden, J., Cavanagh, M. M., McNamee, K., McCann, F., Snelgrove, R. J., Shaw, S., Feldmann, M., Taylor, P. C., Horwood, N. J., Hussell, T. 2014

    Abstract

    An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk. Approaches that might specifically reduce autoimmunity and tissue damage without infectious risk would be important. Here we describe that TNF superfamily member OX40 ligand (OX40L; CD252), which is expressed predominantly on antigen-presenting cells, and its receptor OX40 (on activated T cells), are restricted to the inflamed joint in arthritis in mice with collagen-induced arthritis and humans with RA. Blockade of this pathway in arthritic mice reduced inflammation and restored tissue integrity predominantly by inhibiting inflammatory cytokine production by OX40L-expressing macrophages. Furthermore, we identify a previously unknown role for OX40L in steady-state bone homeostasis. This work shows that more targeted approaches may augment the "therapeutic window" and increase the benefit/risk in RA, and possibly other autoimmune diseases, and are thus worth testing in humans.

    View details for DOI 10.1073/pnas.1321071111

    View details for PubMedID 24469824

  • IL-7-and IL-15-Mediated TCR Sensitization Enables T Cell Responses to Self-Antigens JOURNAL OF IMMUNOLOGY Deshpande, P., Cavanagh, M. M., Le Saux, S., Singh, K., Weyand, C. M., Goronzy, J. J. 2013; 190 (4): 1416-1423

    Abstract

    Regulation of the ERK pathway is intimately involved in determining whether TCR stimulation is productive or induces anergy. T cells from patients with rheumatoid arthritis (RA) have increased ERK responsiveness, which may be relevant for disease pathogenesis. Inflammatory cytokines such as TNF-? did not reproduce the TCR hypersensitivity typical for RA in T cells from healthy individuals. In contrast, priming with the homeostatic cytokines (HCs) IL-7 and IL-15 amplified ERK phosphorylation to TCR stimulation 2- to 3-fold. The underlying mechanism involved a priming of the SOS-dependent amplification loop of RAS activation. The sensitization of the TCR signaling pathway has downstream consequences, such as increased proliferation and preferential Th1 differentiation. Importantly, priming with IL-7 or IL-15 enabled T cell responses to autoantigens associated with RA. Production of HCs is induced in lymphopenic conditions, which have been shown to predispose for autoimmunity and which appear to be present in the preclinical stages of RA. We propose that HCs, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA.

    View details for DOI 10.4049/jimmunol.1201620

    View details for Web of Science ID 000314825400005

    View details for PubMedID 23325887

  • Systems Biology of Vaccination in the Elderly SYSTEMS BIOLOGY Duraisingham, S. S., Rouphael, N., Cavanagh, M. M., Nakaya, H. I., Goronzy, J. J., Pulendran, B. 2013; 363: 117-142

    Abstract

    Aging population demographics, combined with suboptimal vaccine responses in the elderly, make the improvement of vaccination strategies in the elderly a developing public health issue. The immune system changes with age, with innate and adaptive cell components becoming increasingly dysfunctional. As such, vaccine responses in the elderly are impaired in ways that differ depending on the type of vaccine (e.g., live attenuated, polysaccharide, conjugate, or subunit) and the mediators of protection (e.g., antibody and/or T cell). The rapidly progressing field of systems biology has been shown to be useful in predicting immunogenicity and offering insights into potential mechanisms of protection in young adults. Future application of systems biology to vaccination in the elderly may help to identify gene signatures that predict suboptimal responses and help to identify more accurate correlates of protection. Moreover, the identification of specific defects may be used to target novel vaccination strategies that improve efficacy in elderly populations.

    View details for DOI 10.1007/82_2012_250

    View details for Web of Science ID 000330590200008

    View details for PubMedID 22903566

  • Chronic inflammation and aging: DNA damage tips the balance CURRENT OPINION IN IMMUNOLOGY Cavanagh, M. M., Weyand, C. M., Goronzy, J. J. 2012; 24 (4): 488-493

    Abstract

    The aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanisms behind the amplified inflammatory profile of aged adaptive immunity, and the reciprocal relationship between chronic inflammation and immune aging. Aged hematopoietic stem cells are driven to differentiate following accumulated DNA damage, thus depleting the stem cell pool and increasing the number of damaged effector cells in the circulation. Chronic DNA damage responses in lymphocytes as well as senescent cells of other lineages initiate the production of inflammatory mediators. In addition, aged lymphocytes become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity.

    View details for DOI 10.1016/j.coi.2012.04.003

    View details for Web of Science ID 000308898700020

    View details for PubMedID 22565047

  • K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Singh, K., Deshpande, P., Li, G., Yu, M., Pryshchep, S., Cavanagh, M., Weyand, C. M., Goronzy, J. J. 2012; 109 (25): E1629-E1637

    Abstract

    Autoantibodies to common autoantigens and neoantigens, such as IgG Fc and citrullinated peptides, are immunological hallmarks of rheumatoid arthritis (RA). We examined whether a failure in maintaining tolerance is mediated by defects in T-cell receptor activation threshold settings. RA T cells responded to stimulation with significantly higher ERK phosphorylation (P < 0.001). Gene expression arrays of ERK pathway members suggested a higher expression of KRAS and BRAF, which was confirmed by quantitative PCR (P = 0.003), Western blot, and flow cytometry (P < 0.01). Partial silencing of KRAS and BRAF lowered activation-induced phosphorylated ERK levels (P < 0.01). In individual cells, levels of these signaling molecules correlated with ERK phosphorylation, attesting that their concentrations are functionally important. In confocal studies, B-RAF/K-RAS clustering was increased in RA T cells 2 min after T-cell receptor stimulation (P < 0.001). Overexpression of B-RAF and K-RAS in normal CD4 T cells amplified polyclonal T-cell proliferation and facilitated responses to citrullinated peptides. We propose that increased expression of B-RAF and K-RAS lowers T-cell activation thresholds in RA T cells, enabling responses to autoantigens.

    View details for DOI 10.1073/pnas.1117640109

    View details for Web of Science ID 000306061400009

    View details for PubMedID 22615393

  • Finding Balance: T cell Regulatory Receptor Expression during Aging. Aging and disease Cavanagh, M. M., Qi, Q., Weyand, C. M., Goronzy, J. J. 2011; 2 (5): 398-413

    Abstract

    Aging is associated with a variety of changes to immune responsiveness. Reduced protection against infection, reduced responses to vaccination and increased risk of autoimmunity are all hallmarks of advanced age. Here we consider how changes in the expression of regulatory receptors on the T cell surface contribute to altered immunity during aging.

    View details for PubMedID 22396890

  • The innate immune rheostat: influence on lung inflammatory disease and secondary bacterial pneumonia BIOCHEMICAL SOCIETY TRANSACTIONS Hussell, T., Cavanagh, M. M. 2009; 37: 811-813

    Abstract

    The activity of innate immunity is not simply dictated by the presence of an antigen but also by the balance between negative regulatory and immune potentiator pathways. Even in the absence of antigen, innate immunity can 'inflame' if negative regulators are absent. This resting state is adaptable and dictated by environmental influences, host genetics and past infection history. A return to homoeostasis post inflammation may therefore not leave the tissue in an identical state to that prior to the inflammatory event. This adaptability makes us all unique and also explains the variable outcome experienced by a diverse population to the same inflammatory stimulus. Using murine models we have identified that influenza virus causes a long-term modification of the lung microenvironment by a de-sensitization to bacterial products and an increase in the myeloid negative regulator CD200R (CD200 receptor). These two events prevent subsequent inflammatory damage while the lung is healing, but also they may predispose to bacterial colonization of the lower respiratory tract should regulatory mechanisms overshoot. In the extreme, this leads to bacterial pneumonia, sepsis and death. A deeper understanding of the consequences arising from innate immune cell alteration during influenza infection and the subsequent development of bacterial complications has important implications for future drug development.

    View details for DOI 10.1042/BST0370811

    View details for Web of Science ID 000268902800033

    View details for PubMedID 19614599

  • Is it wise to target the late costimulatory molecule OX40 as a therapeutic target? ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS Cavanagh, M. M., Hussell, T. 2008; 56 (5): 291-297

    Abstract

    The immune response triggered following pathogen recognition, though required to clear the infection, can be detrimental if it is produced in excess or fails to resolve promptly. Excessive inflammation contributes to infectious and noninfectious pathologies in the gut (such as inflammatory bowel disease), lung (such as bronchiolitis), and in a variety of autoimmune conditions. T cells contribute significantly to pathology during inflammation. Global anti-inflammatory strategies can alleviate the consequences of exuberant inflammation by suppressing T cell activity, but may leave the patient vulnerable to opportunistic infection. More specific therapies aim to suppress only those T cells involved in the disease process, and one such approach is to target late costimulatory molecules. These are not expressed on nave or resting memory cells. Rather, they have a specific window of expression and their ligation results in the production of abundant inflammatory cytokines. By targeting these molecules, it is hoped that inflammation will reduce, but that therapies will be specific enough to avoid, global immune suppression. This review focuses on the late costimulatory molecule OX40, compare it with other T cell costimulators, and highlight why it is a more suitable target for immune intervention than other immune suppressive strategies.

    View details for DOI 10.1007/s00005-008-0032-3

    View details for Web of Science ID 000260080700001

    View details for PubMedID 18836863

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