Clinical Focus

  • Gastroenterology
  • Inflammatory Bowel Diseases

Academic Appointments

Administrative Appointments

  • Associate Professor of Medicine, Division of Gastroenterology & Hepatology, Stanford University (2017 - Present)
  • Member, National Scientific Advisory Committee (Crohn's and Colitis Foundation of America, CCFA) (2015 - 2018)
  • Member, Clinical, Integrative and Molecular Gastroenterology Study Section (NIH) (2012 - Present)
  • Editorial Board, Gastroenterology (2011 - Present)
  • Member, Immunology Postgraduate Program Committee, Stanford University (2011 - 2014)
  • Assistant Professor of Medicine, Division of Gastroenterology & Hepatology, Stanford University (2010 - 2017)
  • Editorial Board, Digestive Diseases and Sciences (2008 - 2013)
  • Instructor, Division of Gastroenterology & Hepatology, Stanford University (2007 - 2010)

Honors & Awards

  • Synergy Award, Kenneth Rainin Foundation (2017 - 2019)
  • Inducted to The American Society for Clinical Investigation, ASCI (2017)
  • Endowed Ballinger-Swindells Family Scholar, Stanford University (2016 - Present)
  • Immunology Faculty Mentor of the Year, Stanford University (2015 - 2016)
  • Division Teaching Award, Stanford University (2013)
  • Harold Amos Medical Faculty Development Award, Robert Wood Johnson Foundation (2011-2015)
  • DDC Named Investigator, Stanford Digestive Disease Center (DDC) (2010-2011)
  • Pilot/Feasibility Award, Stanford Digestive Disease Center (2007-2008)
  • Clinical Scientist Career Development Award (K08), NIH/NIDDK (2006-2011)

Professional Education

  • Medical Education:McMaster University Michael G DeGroote School of Medicine Registrar (1996) Canada
  • Fellowship:Stanford University School of Medicine (2005) CA
  • Board Certification: Gastroenterology, American Board of Internal Medicine (2007)
  • Postdoctoral Research Fellowship, Stanford, University (2006)
  • Board Certification, Gastroenterology, Royal College of Physicians of Canada (2002)
  • Fellowship:University of Toronto (2002) Canada
  • Board Certification, Internal Medicine: American Board of Internal Medicine &, Royal College of Physicians of Canada (1999)
  • Residency:University of Western Ontario (1999) Canada

Research & Scholarship

Current Research and Scholarly Interests

Leukocyte recruitment & immune responses in diseases affecting digestive organs

Clinical Trials

  • Localized Therapeutics for the Treatment of Gastrointestinal Disorders Recruiting

    The purpose of this study is to determine the patient preference for a biocompatible thermosensitive solution-gel versus water or saline (liquid) enema.

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2017-18 Courses

Stanford Advisees

Graduate and Fellowship Programs


All Publications

  • Editors' Introduction to the Chronic Pancreatitis and Pancreatic Cysts Special Issue. Digestive diseases and sciences Park, W. G., Habtezion, A. 2017

    View details for DOI 10.1007/s10620-017-4613-z

    View details for PubMedID 28523572

  • Trafficking receptor signatures define blood plasmablasts responding to tissue-specific immune challenge. JCI insight Seong, Y., Lazarus, N. H., Sutherland, L., Habtezion, A., Abramson, T., He, X., Greenberg, H. B., Butcher, E. C. 2017; 2 (6)


    Antibody-secreting cells are generated in regional lymphoid tissues and traffic as plasmablasts (PBs) via lymph and blood to target sites for local immunity. We used multiparameter flow cytometry to define PB trafficking programs (TPs, combinations of adhesion molecules and chemoattractant receptors) and their imprinting in patients in response to localized infection or immune insults. TPs enriched after infection or autoimmune inflammation of mucosae correlate with sites of immune response or symptoms, with different TPs imprinted during small intestinal, colon, throat, and upper respiratory immune challenge. PBs induced after intramuscular or intradermal influenza vaccination, including flu-specific antibody-secreting cells, display TPs characterized by the lack of mucosal homing receptors. PBs of healthy donors display diverse mucosa-associated TPs, consistent with homeostatic immune activity. Identification of TP signatures of PBs may facilitate noninvasive monitoring of organ-specific immune responses.

    View details for DOI 10.1172/jci.insight.90233

    View details for PubMedID 28352656

  • Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut Becker, L., Nguyen, L., Gill, J., Kulkarni, S., Pasricha, P. J., Habtezion, A. 2017


    The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS.Longitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR.Ageing causes a shift in macrophage polarisation from anti-inflammatory 'M2' to proinflammatory 'M1' that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS.A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

    View details for DOI 10.1136/gutjnl-2016-312940

    View details for PubMedID 28228489

  • Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. The lancet. Gastroenterology & hepatology Hart, P. A., Bellin, M. D., Andersen, D. K., Bradley, D., Cruz-Monserrate, Z., Forsmark, C. E., Goodarzi, M. O., Habtezion, A., Korc, M., Kudva, Y. C., Pandol, S. J., Yadav, D., Chari, S. T. 2016; 1 (3): 226-237


    Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

    View details for DOI 10.1016/S2468-1253(16)30106-6

    View details for PubMedID 28404095

  • Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., Habtezion, A. 2016


    Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4(+) T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I ?1 chain, but not ?2 smooth muscle actin or transforming growth factor-?. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

    View details for DOI 10.1053/j.gastro.2016.09.064

    View details for PubMedID 27769811

  • Macrophages and pancreatic ductal adenocarcinoma. Cancer letters Habtezion, A., Edderkaoui, M., Pandol, S. J. 2016; 381 (1): 211-216


    Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor-associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer.

    View details for DOI 10.1016/j.canlet.2015.11.049

    View details for PubMedID 26708507

  • Reactive Oxygen Species Imaging in a Mouse Model of Inflammatory Bowel Disease MOLECULAR IMAGING AND BIOLOGY Bronsart, L., Linh Nguyen, L., Habtezion, A., Contag, C. 2016; 18 (4): 473-478


    Reactive oxygen species (ROS) are important contributors to inflammatory bowel disease (IBD); however, there are insufficient tools for their in vivo evaluation.To determine if a chemiluminescent ROS reporter, coelenterazine, would be a useful tool for the detection of immune cell activation, the macrophage cell line (RAW 264.7) was treated with phorbol myristate acetate (PMA). Additionally, coelenterazine was used to monitor the changes in ROS production over time in a mouse model of IBD.In vitro, coelenterazine enabled the dynamic monitoring of the RAW 264.7 cell oxidative burst. In vivo, there were early, preclinical, changes in the localization and magnitude of coelenterazine chemiluminescent foci.Coelenterazine offers a high-throughput method for assessing immune cell activation in culture and provides a means for the in vivo detection and localization of ROS during IBD disease progression.

    View details for DOI 10.1007/s11307-016-0934-0

    View details for Web of Science ID 000379191800001

    View details for PubMedID 26873653

  • HDAC3 mediates smoking-induced pancreatic cancer ONCOTARGET Edderkaoui, M., Xu, S., Chheda, C., Morvaridi, S., Hu, R. W., Grippo, P. J., Mascarinas, E., Principe, D. R., Knudsen, B., Xue, J., Habtezion, A., Uyeminami, D., Pinkerton, K. E., Pandol, S. J. 2016; 7 (7): 7747-7760
  • Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology Habtezion, A., Nguyen, L. P., Hadeiba, H., Butcher, E. C. 2016; 150 (2): 340-354


    Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate inflammation. A wide array of chemoattractants, chemoattractant receptors, and adhesion molecules expressed by leukocytes, mucosal endothelium, epithelium, and stromal cells controls leukocyte recruitment and microenvironmental localization in intestine and in the gut-associated lymphoid tissues (GALTs). Naive lymphocytes traffic to the gut-draining mesenteric lymph nodes where they undergo antigen-induced activation and priming; these processes determine their memory/effector phenotypes and imprint them with the capacity to migrate via the lymph and blood to the intestines. Mechanisms of T-cell recruitment to GALT and of T cells and plasmablasts to the small intestine are well described. Recent advances include the discovery of an unexpected role for lectin CD22 as a B-cell homing receptor GALT, and identification of the orphan G-protein-coupled receptor 15 (GPR15) as a T-cell chemoattractant/trafficking receptor for the colon. GPR15 decorates distinct subsets of T cells in mice and humans, a difference in species that could affect translation of the results of mouse colitis models to humans. Clinical studies with antibodies to integrin ?4?7 and its vascular ligand mucosal vascular addressin cell adhesion molecule 1 are proving the value of lymphocyte trafficking mechanisms as therapeutic targets for inflammatory bowel diseases. In contrast to lymphocytes, cells of the innate immune system express adhesion and chemoattractant receptors that allow them to migrate directly to effector tissue sites during inflammation. We review the mechanisms for innate and adaptive leukocyte localization to the intestinal tract and GALT, and discuss their relevance to human intestinal homeostasis and inflammation.

    View details for DOI 10.1053/j.gastro.2015.10.046

    View details for PubMedID 26551552

  • Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice FASEB JOURNAL Toivola, D. M., Habtezion, A., Misiorek, J. O., Zhang, L., Nystrom, J. H., Sharpe, O., Robinson, W. H., Kwan, R., Omary, M. B. 2015; 29 (12): 5081-5089

    View details for DOI 10.1096/fj.14-269795

    View details for Web of Science ID 000365523600031

    View details for PubMedID 26399787

  • Inflammation in acute and chronic pancreatitis. Current opinion in gastroenterology Habtezion, A. 2015; 31 (5): 395-399


    This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis.Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation.Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.

    View details for DOI 10.1097/MOG.0000000000000195

    View details for PubMedID 26107390

  • A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies. Gastroenterology Sinha, S. R., Nguyen, L. P., Inayathullah, M., Malkovskiy, A., Habte, F., Rajadas, J., Habtezion, A. 2015; 149 (1): 52-55 e2


    Systemic therapies for inflammatory bowel disease are associated with increased risk of infections and malignancies. Topical therapies reduce systemic exposure, but can be difficult to retain or have limited proximal distribution. To mitigate these issues, we developed a thermo-sensitive platform, using a polymer-based system that is liquid at room temperature but turns into a viscous gel upon reaching body temperature. Following rectal administration to mice with dextran sulphate sodium-induced colitis, the platform carrying budesonide or mesalamine becomes more viscoelastic near body temperature. Mice given the drug-containing platform gained more weight and had reduced histologic and biologic features of colitis than mice given the platform alone or liquid drugs via enema. Image analysis showed that enemas delivered with and without the platform reached similar distances in the colons of mice, but greater colonic retention was achieved by using the platform.

    View details for DOI 10.1053/j.gastro.2015.04.002

    View details for PubMedID 25863215

  • Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism MOLECULAR BIOLOGY OF THE CELL Helenius, T. O., Misiorek, J. O., Nystrom, J. H., Fortelius, L. E., Habtezion, A., Liao, J., Asghar, M. N., Zhang, H., Azhar, S., Omary, M. B., Toivola, D. M. 2015; 26 (12): 2298-2310


    Simple-type epithelial keratins are intermediate filament proteins important for mechanical stability and stress protection. Keratin mutations predispose to human liver disorders, whereas their roles in intestinal diseases are unclear. Absence of keratin 8 (K8) in mice leads to colitis, decreased Na/Cl uptake, protein mistargeting, and longer crypts, suggesting that keratins contribute to intestinal homeostasis. We describe the rate-limiting enzyme of the ketogenic energy metabolism pathway, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated protein in the K8-knockout (K8(-/-)) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in dextran sulfate sodium-induced colitis. Peroxisome proliferator-activated receptor ?, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions-starvation or ketogenic diet-increase K8(+/+) HMGCS2, whereas this response is blunted in the K8(-/-) colon. Microbiota-produced short-chain fatty acids (SCFAs), substrates in the colonic ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-butyrate producers in the colon, were not altered in the K8(-/-). In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8(-/-) colonocytes, suggesting a role for keratins in colonocyte energy metabolism and homeostasis.

    View details for DOI 10.1091/mbc.E14-02-0736

    View details for Web of Science ID 000357037300013

    View details for PubMedID 25904331

  • Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis NATURE COMMUNICATIONS Xue, J., Sharma, V., Hsieh, M. H., Chawla, A., Murali, R., Pandol, S. J., Habtezion, A. 2015; 6


    Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4R?, myeloid-specific IL-4R? and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

    View details for DOI 10.1038/ncomms8158

    View details for Web of Science ID 000355534000005

    View details for PubMedID 25981357

  • Protective role of hemeoxygenase-1 in gastrointestinal diseases. Cellular and molecular life sciences Chang, M., Xue, J., Sharma, V., Habtezion, A. 2015; 72 (6): 1161-1173


    Disorders and diseases of the gastrointestinal system encompass a wide array of pathogenic mechanisms as a result of genetic, infectious, neoplastic, and inflammatory conditions. Inflammatory diseases in general are rising in incidence and are emerging clinical problems in gastroenterology and hepatology. Hemeoxygenase-1 (HO-1) is a stress-inducible enzyme that has been shown to confer protection in various organ-system models. Its downstream effectors, carbon monoxide and biliverdin have also been shown to offer these beneficial effects. Many studies suggest that induction of HO-1 expression in gastrointestinal tissues and cells plays a critical role in cytoprotection and resolving inflammation as well as tissue injury. In this review, we examine the protective role of HO-1 and its downstream effectors in modulating inflammatory diseases of the upper (esophagus and stomach) and lower (small and large intestine) gastrointestinal tract, the liver, and the pancreas. Cytoprotective, anti-inflammatory, anti-proliferative, antioxidant, and anti-apoptotic activities of HO-1 make it a promising if not ideal therapeutic target for inflammatory diseases of the gastrointestinal system.

    View details for DOI 10.1007/s00018-014-1790-1

    View details for PubMedID 25428780

  • Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nature immunology Nguyen, L. P., Pan, J., Dinh, T. T., Hadeiba, H., O'Hara, E., Ebtikar, A., Hertweck, A., Gökmen, M. R., Lord, G. M., Jenner, R. G., Butcher, E. C., Habtezion, A. 2015; 16 (2): 207-213


    Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (Treg) cells. The TH2 transcriptional activator GATA-3 and the Treg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis.

    View details for DOI 10.1038/ni.3079

    View details for PubMedID 25531831

  • Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins. Chemistry & biology Segal, E., Prestwood, T. R., van der Linden, W. A., Carmi, Y., Bhattacharya, N., Withana, N., Verdoes, M., Habtezion, A., Engleman, E. G., Bogyo, M. 2015; 22 (1): 148-158


    Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

    View details for DOI 10.1016/j.chembiol.2014.11.008

    View details for PubMedID 25579207

    View details for PubMedCentralID PMC4353655

  • Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nature communications Xue, J., Sharma, V., Hsieh, M. H., Chawla, A., Murali, R., Pandol, S. J., Habtezion, A. 2015; 6: 7158-?


    Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4R?, myeloid-specific IL-4R? and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

    View details for DOI 10.1038/ncomms8158

    View details for PubMedID 25981357

  • Pharmacologic therapy for acute pancreatitis WORLD JOURNAL OF GASTROENTEROLOGY Kambhampati, S., Park, W., Habtezion, A. 2014; 20 (45): 16868-16880
  • Immune cells and immune-based therapy in pancreatitis. Immunologic research Xue, J., Sharma, V., Habtezion, A. 2014; 58 (2-3): 378-386


    Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.

    View details for DOI 10.1007/s12026-014-8504-5

    View details for PubMedID 24710635

  • Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition JOURNAL OF CLINICAL INVESTIGATION Xue, J., Habtezion, A. 2014; 124 (1): 437-447


    The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and CO-primed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-? secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile- and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO- or CO-RM-mediated toxicities in AP and a wide range of diseases.

    View details for DOI 10.1172/JCI71362

    View details for Web of Science ID 000329333500048

    View details for PubMedID 24334457

  • Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells. Mucosal immunology Zeng, R., Oderup, C., Yuan, R., Lee, M., Habtezion, A., Hadeiba, H., BUTCHER, E. C. 2013; 6 (4): 847-856


    The vitamin A metabolite retinoic acid (RA) regulates intestinal immune responses through immunomodulatory actions on intestinal dendritic cells (DCs) and lymphocytes. Here, we show that RA also controls the generation of gut-tropic migratory DC precursors, referred to as pre-mucosal DCs (pre-?DCs). Pre-?DCs express the gut trafficking receptor ?4?7 and home preferentially to the intestines. They develop in the bone marrow (BM), can differentiate into CCR9? plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to CD103? intestinal cDCs. Generation of pre-?DCs in vivo in the BM or in vitro is regulated by RA and RA receptor ? (RAR?) signaling. The frequency of pre-?DCs is reduced in vitamin A-deficient animals and in animals treated with RAR inhibitors. The results define a novel vitamin A-dependent, RA-regulated developmental sequence for DCs and identify a targeted precursor for CD103? cDCs in the gut.

    View details for DOI 10.1038/mi.2012.123

    View details for PubMedID 23235743

    View details for PubMedCentralID PMC3612556

  • Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology Zheng, L., Xue, J., Jaffee, E. M., Habtezion, A. 2013; 144 (6): 1230-1240


    Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.

    View details for DOI 10.1053/j.gastro.2012.12.042

    View details for PubMedID 23622132

  • Aryl Hydrocarbon Receptor Regulates Pancreatic IL-22 Production and Protects Mice From Acute Pancreatitis GASTROENTEROLOGY Xue, J., Nguyen, D. T., Habtezion, A. 2012; 143 (6): 1670-1680


    The type of immune response during development of acute pancreatitis (AP) determines disease severity. Pancreatic epithelial cells express the interleukin (IL)-22 receptor A1 (IL-22RA1). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates expression of IL-22. We investigated sources and role of IL-22 in the pancreas, along with the effects of AhR activation on IL-22 expression and AP progression in mice.We analyzed the effects of recombinant IL-22, a monoclonal antibody against IL-22, and agonists and antagonists of AhR in mice with AP (induced with caerulein or a choline-deficient diet supplemented with DL-ethionine) and control mice. We also analyzed transgenic mice with AhR deficiency (AhR(d) and AhR(-/-) mice).CD4(+) T cells were the main source of IL-22 in pancreatic tissues from healthy mice. During development of AP, numbers of IL-22(+) CD4(+) T cells were reduced, whereas IL-22RA1 was up-regulated. Consistent with high levels of IL-22RA1 expression, pancreatic acinar cells responded to IL-22 signaling via signal transducers and activators of transcription 3; administration of IL-22 reduced AP and associated lung injury in mice. AhR was required for production of IL-22 and protected mice from AP. Mice that did not respond to AhR activation developed AP, but administration of IL-22 reduced AP; blockade of IL-22 reversed the ability of activated AhR to protect against AP.AhR activation protects mice from AP by inducing expression of IL-22. AhR therefore mediates interactions between pancreatic leukocytes and epithelial cells and might be developed as a therapeutic target.

    View details for DOI 10.1053/j.gastro.2012.08.051

    View details for Web of Science ID 000311505100044

    View details for PubMedID 23022954

  • Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance IMMUNITY Hadeiba, H., Lahl, K., Edalati, A., Oderup, C., Habtezion, A., Pachynski, R., Nguyen, L., Ghodsi, A., Adler, S., Butcher, E. C. 2012; 36 (3): 438-450


    Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.

    View details for DOI 10.1016/j.immuni.2012.01.017

    View details for Web of Science ID 000302048400015

    View details for PubMedID 22444632

  • Panhematin provides a therapeutic benefit in experimental pancreatitis GUT Habtezion, A., Kwan, R., Akhtar, E., Wanaski, S. P., Collins, S. D., Wong, R. J., Stevenson, D. K., Butcher, E. C., Omary, M. B. 2011; 60 (5): 671-679


    Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNF?. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1)(+) macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis.We defined the distribution of radiolabelled haemin, then used in vivo HO-1-luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay.Intravenously administered Panhematin induces rapid recruitment of HO-1(+) cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant.Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1(+) cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis.

    View details for DOI 10.1136/gut.2010.217208

    View details for Web of Science ID 000289076700015

    View details for PubMedID 21159893

  • Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Habtezion, A., Toivola, D. M., Asghar, M. N., Kronmal, G. S., Brooks, J. D., Butcher, E. C., Omary, M. B. 2011; 108 (4): 1445-1450


    Keratin 8 (K8) is a major intermediate filament protein present in enterocytes and serves an antiapoptotic function in hepatocytes. K8-null mice develop colonic hyperplasia and colitis that are reversed after antibiotic treatment. To investigate the pathways that underlie the mechanism of colonocyte hyperplasia and the normalization of the colonic phenotype in response to antibiotics, we performed genome-wide microarray analysis. Functional annotation of genes that are differentially regulated in K8(-/-) and K8(+/+) isolated colon crypts (colonocytes) identified apoptosis as a major altered pathway. Exposure of K8(-/-) colonocytes or colon organ ("organoid") cultures, but not K8(-/-) small intestine organoid cultures, to apoptotic stimuli showed, surprisingly, that they are resistant to apoptosis compared with their wild-type counterparts. This resistance is not related to inflammation per se because T-cell receptor ?-null (TCR-?(-/-)) and wild-type colon cultures respond similarly upon induction of apoptosis. Following antibiotic treatment, K8(-/-) colonocytes and organ cultures become less resistant to apoptosis and respond similarly to the wild-type colonocytes. Antibiotics also normalize most differentially up-regulated genes, including survivin and ?4-integrin. Treatment of K8(-/-) mice with anti-?4-integrin antibody up-regulated survivin, and induced phosphorylation of focal adhesion kinase with decreased activation of caspases. Therefore, unlike the proapoptotic effect of K8 mutation or absence in hepatocytes, lack of K8 confers resistance to colonocyte apoptosis in a microflora-dependent manner.

    View details for DOI 10.1073/pnas.1010833108

    View details for Web of Science ID 000286594800046

    View details for PubMedID 21220329

    View details for PubMedCentralID PMC3029736

  • Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Habtezion, A., Kwan, R., Yang, A. L., Morgan, M. E., Akhtar, E., Wanaski, S. P., Collins, S. D., Butcher, E. C., Kamal, A., Omary, M. B. 2011; 300 (1): G12-G20


    Heme oxygenase-1 (HO-1) induction by hemin or Panhematin protects against experimental pancreatitis. As a preclinical first step toward determining whether HO-1 upregulation is a viable target in acute pancreatitis (AP) patients, we tested the hypothesis that HO-1 expression in peripheral blood mononuclear cell (PBMC) subsets of hospitalized patients with mild AP is upregulated then normalizes upon recovery and that cells from AP patients have the potential to upregulate their HO-1 ex vivo if exposed to Panhematin. PBMCs were isolated on days 1 and 3 of hospitalization from the blood of 18 AP patients, and PMBC HO-1 levels were compared with PMBCs of 15 hospitalized controls (HC) and 7 volunteer healthy controls (VC). On day 1 of hospitalization, AP patients compared with VCs had higher HO-1 expression in monocytes and neutrophils. Notably, AP monocyte HO-1 levels decreased significantly upon recovery. Panhematin induced HO-1 in ex vivo cultured AP PBMCs more readily than in HC or VC PBMCs. Furthermore, PBMCs from acutely ill AP patients on day 1 were more responsive to HO-1 induction compared with day 3 upon recovery. Similarly, mouse splenocytes had enhanced HO-1 inducibility as their pancreatitis progressed from mild to severe. In conclusion, AP leads to reversible PBMC HO-1 upregulation that is associated with clinical improvement and involves primarily monocytes. Leukocytes from AP patients or mice with AP are primed for HO-1 induction by Panhematin, which suggests that Panhematin could offer a therapeutic benefit.

    View details for DOI 10.1152/ajpgi.00231.2010

    View details for Web of Science ID 000285744300002

    View details for PubMedID 20966033

  • Diabetic Gastroparesis: An Emerging Role for Macrophages and Heme Oxygenase-1 GASTROENTEROLOGY Habtezion, A., Wiley, J. W. 2010; 138 (7): 2219-2223

    View details for DOI 10.1053/j.gastro.2010.04.028

    View details for Web of Science ID 000278136900010

    View details for PubMedID 20434508

  • Intermediate filaments take the heat as stress proteins TRENDS IN CELL BIOLOGY Toivola, D. M., Strnad, P., Habtezion, A., Omary, M. B. 2010; 20 (2): 79-91


    Intermediate filament (IF) proteins and heat shock proteins (HSPs) are large multimember families that share several features, including protein abundance, significant upregulation in response to a variety of stresses, cytoprotective functions, and the phenocopying of several human diseases after IF protein or HSP mutation. We are now coming to understand that these common elements point to IFs as important cellular stress proteins with some roles akin to those already well-characterized for HSPs. Unique functional roles for IFs include protection from mechanical stress, whereas HSPs are characteristically involved in protein folding and as chaperones. Shared IF and HSP cytoprotective roles include inhibition of apoptosis, organelle homeostasis, and scaffolding. In this report, we review data that corroborate the view that IFs function as highly specialized cytoskeletal stress proteins that promote cellular organization and homeostasis.

    View details for DOI 10.1016/j.tcb.2009.11.004

    View details for Web of Science ID 000275156700004

    View details for PubMedID 20045331

  • Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis JOURNAL OF CELL SCIENCE Tao, G., Looi, K. S., Toivola, D. M., Strnad, P., Zhou, Q., Liao, J., Wei, Y., Habtezion, A., Omary, M. B. 2009; 122 (21): 3851-3855


    Absence or mutation of keratins 8 (K8) or 18 (K18) cause predisposition to liver injury and apoptosis. We assessed the mechanisms of hepatocyte keratin-mediated cytoprotection by comparing the protein expression profiles of livers from wild-type and K8-null mice using two-dimensional differential-in-gel-electrophoresis (2D-DIGE) and mass spectrometry. Prominent among the alterations were those of mitochondrial proteins, which were confirmed using 2D-DIGE of purified mitochondria. Ultrastructural analysis showed that mitochondria of livers that lack or have disrupted keratins are significantly smaller than mitochondria of wild-type livers. Immunofluorescence staining showed irregular distribution of mitochondria in keratin-absent or keratin-mutant livers. K8-null livers have decreased ATP content; and K8-null mitochondria have less cytochrome c, increased release of cytochrome c after exposure to Ca(2+) and oxidative stimulation, and a higher sensitivity to Ca(2+)-induced permeability transition. Therefore, keratins play a direct or indirect role in regulating the shape and function of mitochondria. The effects of keratin mutation on mitochondria are likely to contribute to hepatocyte predisposition to apoptosis and oxidative injury, and to play a pathogenic role in keratin-mutation-related human liver disease.

    View details for DOI 10.1242/jcs.051862

    View details for Web of Science ID 000271475600004

    View details for PubMedID 19825937

  • CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease NATURE IMMUNOLOGY Hadeiba, H., Sato, T., Habtezion, A., Oderup, C., Pan, J., Butcher, E. C. 2008; 9 (11): 1253-1260


    Dendritic cells (DCs) are 'professional' antigen-presenting cells that are key in the regulation of immune responses. Here we characterize a unique subset of tolerogenic DCs that expressed the chemokine receptor CCR9 and migrated to the CCR9 ligand CCL25, a chemokine linked to the homing of T cells and DCs to the gut. CCR9(+) DCs were of the plasmacytoid DC (pDC) lineage, had an immature phenotype and rapidly downregulated CCR9 in response to maturation-inducing pDC-restricted Toll-like receptor ligands. CCR9(+) pDCs were potent inducers of regulatory T cell function and suppressed antigen-specific immune responses both in vitro and in vivo, including inhibiting acute graft-versus-host disease induced by allogeneic CD4(+) donor T cells in irradiated recipients. Our results identify a highly immunosuppressive population of pDCs present in lymphoid tissues.

    View details for DOI 10.1038/ni.1658

    View details for Web of Science ID 000260248600012

    View details for PubMedID 18836452

    View details for PubMedCentralID PMC2901237

  • DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27 NATURE IMMUNOLOGY Sigmundsdottir, H., Pan, J., Debes, G. F., Alt, C., Habtezion, A., Soler, D., Butcher, E. C. 2007; 8 (3): 285-293


    During adaptive immune responses, dendritic cells activate T cells and endow them with specific homing properties. Mechanisms that 'imprint' specific tropisms, however, are not well defined. We show here that 1,25(OH)(2)D(3), the active form of vitamin D3, signaled T cells to express CC chemokine receptor 10, which enabled them to migrate to the skin-specific chemokine CCL27 secreted by keratinocytes of the epidermis. In contrast, 1,25(OH)(2)D(3) suppressed the gut-homing receptors alpha4beta7 and CCR9. Vitamin D3, the inactive prohormone naturally generated in the skin by exposure to the sun, was processed by dendritic cells and T cells to the active metabolite, providing a mechanism for the local regulation of T cell 'epidermotropism'. Our findings support a model in which dendritic cells process and 'interpret' locally produced metabolites to 'program' T cell homing and microenvironmental positioning.

    View details for DOI 10.1038/ni1433

    View details for Web of Science ID 000244275100014

    View details for PubMedID 17259988

  • Short-term homing assay reveals a critical role for lymphocyte function-associated antigen-1 in the hepatic recruitment of lymphocytes in graft-versus-host disease JOURNAL OF HEPATOLOGY Sato, T., Habtezion, A., Beilhack, A., Schulz, S., Butcher, E., Thorlacius, H. 2006; 44 (6): 1132-1140


    The liver is a major target organ of graft versus host disease (GvHD) with massive infiltration of alloreactive lymphocytes resulting in hepatitis and hepatocyte injury. Although adhesive mechanisms have been implicated in the biology of GvHD hepatitis, the identity of homing receptors involved in the initial recruitment of cells from the blood is not known.We have developed a short-term homing assay in a model of murine GvHD. Splenocytes from donors at an active stage of GvHD were injected intravenously into adoptive recipients also undergoing GvHD. The recruitment of cells to the liver was assessed 6h after cell transfer.Activated donor CD8 and CD4 lymphocytes expressed lymphocyte function antigen-1 (LFA-1), alpha4-integrins, and P-selectin binding ligands, and localized more efficiently than naďve T cells. Immunoneutralization of LFA-1 reduced the recruitment of CD8 and CD4 lymphocytes to the liver by more than 60%. Anti-LFA-1 antibody also markedly reduced infiltration of lymphocytes in periportal areas and protected against hepatocellular damage.We demonstrate a critical role of LFA-1 in the recruitment of activated lymphocytes to the liver and in immune-cell mediated hepatitis. LFA-1 may be an effective therapeutic target for protecting the liver following bone marrow transplantation.

    View details for DOI 10.1016/j.jhep.2005.11.042

    View details for Web of Science ID 000237984400016

    View details for PubMedID 16466827

  • CD8(+) recent thymic emigrants home to and efficiently repopulate the small intestine epithelium NATURE IMMUNOLOGY Staton, T. L., Habtezion, A., Winslow, M. M., Sato, T., Love, P. E., Butcher, E. C. 2006; 7 (5): 482-488


    Prevailing knowledge dictates that naive alphabeta T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8(+) recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and alpha(4)beta(7) integrin were required for gut entry of CD8(+) RTEs. After T cell receptor stimulation, intestinal CD8(+) RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8(+) RTEs efficiently populated the gut of lymphotoxin-alpha-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive alphabeta T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces.

    View details for DOI 10.1038/ni1319

    View details for Web of Science ID 000237008800013

    View details for PubMedID 16582913

  • Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction JOURNAL OF CLINICAL INVESTIGATION Nakamichi, I., Habtezion, A., Zhong, B. H., Contag, C. H., BUTCHER, E. C., Omary, M. B. 2005; 115 (11): 3007-3014


    Hemin upregulates heme oxygenase-1 (HO-1), a stress-induced enzyme implicated in protection from a variety of injuries while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. We show that HO-1 is induced in pancreatitis caused by caerulein and more prominently in severe pancreatitis caused by feeding a choline-deficient diet (CDD). Intraperitoneal hemin administration dramatically increases peritoneal and pancreas macrophages that overexpress HO-1 in association with pancreatic induction of the chemoattractants monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha but not RANTES or macrophage inflammatory protein-2. Hemin administration before CDD feeding protected 8 of 8 mice from lethality while 7 of 16 controls died. Protection is mediated by HO-1-overexpressing macrophages since hemin-primed macrophages home to the pancreas after transfer to naive mice and protect from CDD-induced pancreatitis. Suppression of hemin-primed peritoneal cell HO-1 using HO-1-specific small interfering RNA prior to cell transfer abolishes protection from CDD-induced pancreatitis. Similarly, hemin pretreatment in caerulein-induced pancreatitis reduces serum amylase and lipase, decreases pancreatic trypsin generation, and protects from lung injury. Therefore, hemin-like compounds or hemin-activated macrophages may offer novel therapeutic approaches for preventing acute pancreatitis and its pulmonary complication via upregulation of HO-1.

    View details for DOI 10.1172/JCI24912

    View details for Web of Science ID 000233022100011

    View details for PubMedID 16239966

  • Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments TRENDS IN CELL BIOLOGY Toivola, D. M., Tao, G. Z., Habtezion, A., Liao, J., Omary, M. B. 2005; 15 (11): 608-617


    Intermediate filament proteins (IFs) maintain cell and tissue integrity, based on evidence of their polymerization and mechanical properties, abundance and disease-associated phenotypes. This 'traditional' function is now augmented by organelle-related and protein-targeting roles. Mitochondrial location and function depend on intact IFs, as demonstrated for desmin, keratins and neurofilaments. Golgi positioning is regulated by several IFs, and endosomal/lysosomal protein distribution by vimentin. IFs dramatically affect nuclear function and shape and play a role in subcellular and membrane targeting of proteins. These functions have been noted in tissues but in some cases only in cell culture. The IF-related organelle-specific and protein-targeting roles, which are likely interrelated, provide functions beyond cell scaffolding and integrity and contribute to the cytoprotective and tissue-specific functions of IF proteins.

    View details for Web of Science ID 000233732100008

    View details for PubMedID 16202602

  • Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment JOURNAL OF CELL SCIENCE Habtezion, A., Toivola, D. M., BUTCHER, E. C., Omary, M. B. 2005; 118 (9): 1971-1980


    Keratin 8 (K8) is the major intermediate filament protein present in intestinal epithelia. Depending on the mouse genetic background, absence of K8 causes embryonic lethality or colonic hyperplasia and colitis. We studied disease progression, the inflammatory responses, and role of luminal bacteria in K8-null mice in order to characterize the intestinal pathology of K8-associated colitis. Colon lymphocytes were isolated for analysis of their phenotype and cytokine production, and vascular and lymphocyte adhesion molecule expression in K8-/- mice of varying ages. K8-/- mice had a marked increase in TCR(beta)-positive/CD4-positive T cells infiltrating the colon lamina propria, in association with enhanced Th2 cytokine (IL-4, IL-5 and IL-13) production. K8-/- mice show early signs of inflammation even prior to weaning, that increases with age, and their epithelial cells overexpress MHC class II antigens. The chronic colitis is related to increased CD4-positive infiltrating T cells displaying memory and naive phenotypes, and an altered vascular endothelium with aberrant expression of peripheral node addressin. Analysis of normal gut-specific homing molecules, reveals an increased number of alpha(4)beta(7)-positive cells and vascular mucosal addressin cell adhesion molecule-1 in K8-null colons. Antibiotic treatment markedly decreased colon inflammation and ion transporter AE1/2 mistargeting, indicating that luminal bacteria play an important role in the observed phenotype. Therefore, K8-null mice develop chronic spontaneous Th2-type colitis due to a primary epithelial rather than immune cell defect, which is amenable to antibiotic therapy. These mice provide a model to investigate epithelial-leukocyte and epithelial-microbial cross-talk.

    View details for DOI 10.1242/jcs.02316

    View details for Web of Science ID 000229458700020

    View details for PubMedID 15840656

  • Risk factors for low bone density in Crohn's disease INFLAMMATORY BOWEL DISEASES Habtezion, A., Silverberg, M. S., Parkes, R., Mikolainis, S., Steinhart, A. H. 2002; 8 (2): 87-92


    Osteopenia and osteoporosis are prevalent in patients with Crohn's disease (CD). We conducted a cross-sectional study on consecutive patients with CD to assess the prevalence and factors associated with low bone mass density (BMD). One hundred sixty-eight patients with CD were evaluated. Baseline demographics, medical and surgical history, calcium intake, physical activity, steroid use, Harvey Bradshaw Index, blood and urine tests, and dual-energy X-ray absorptiometry were obtained. Sixty-seven (40%) and seventy-five (45%) patients had osteopenia of the femur and spine, respectively. Ten to 11% of patients had osteoporosis. Of the 40 patients who never used steroids, 19 (48%) had osteopenia of the femur and 12 (30%) of the spine. Significant associations were found between BMD and age, body mass index, and serum magnesium. Lifetime steroid use was a weaker predictor of bone loss. Duration of disease did not correlate with BMD when adjusted for age. At follow-up at a mean of 2 years, BMD declined in the femur but not the spine. However, those with ongoing steroid use had lower spine BMD. A significant number of patients with CD have osteopenia. Age was the most important predictor of bone loss. Significant proportion of steroid naive patients had osteopenia, which implies that mechanisms other than steroid use are also involved in bone loss in CD. Disease activity, systemic inflammation, and hormonal and genetic factors may all be important determinants of bone loss in CD.

    View details for Web of Science ID 000174114900003

    View details for PubMedID 11854605

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