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Mucosal Immunology, Microbial Defense and Inflammatory Bowel Diseases - Reinecker Laboratory

We uncover the genetic basis and molecular mechanisms of microbial recognition and immune regulation in the digestive tract.

The Reinecker laboratory has a long standing interest in basic mechanisms controlling the mucosal immune system, intestinal barrier function and Inflammatory Bowel Diseases (IBD). Dr. Reinecker is an Associate Professor of Medicine at Harvard Medical School and an Associate Immunologist at MGH. Dr. Reinecker is the Director of the Genetics, Genomics and Molecular Biology Core of the Center for the Study of Inflammatory Bowel Diseases (CSIBD) at MGH and the Director for Information Systems for the Division of Gastroenterology at MGH. Current research interests focus on the mechanisms of IBD susceptibility genes in the regulation of the mucosal subspecifications of antigen processing cells for microbial recognition in the intestine. The laboratory has expertise in biochemical and cell biological methods and applies molecular biological approaches to the characterization of the mucosal immune system with particular focus  on mechanisms of macrophage and dendritic cell innate immune function.  Recently, Dr. Reinecker has developed novel 3D and 4D imaging approaches to study membrane trafficking, antigen uptake and cell migration in the mucosal immune system. Many of Dr. Reinecker's post doctoral fellows have gone on to establish their own laboratories studying different aspects of epithelial cell biology and mucosal immunology.

 

Principal Investigator

Dr. Hans-Christian Reinecker

Associate Professor of Medicine
Harvard Medical School
Director Genetics, Genomics and Molecular Biology Core, CSIBD
Associate Immunologist
Massachusetts General Hospital
Gastrointestinal Unit
Jackson bldg. R711
Fruit Street
Boston MA 02114


Email: hans-christian_reinecker@hms.harvard.edu; hreinecker@partners.org


Administrative Assistant

Susan Davis
Email: sjdavis@partners.org
Tel 617-726-3766

Fax 617-726-3673


Post-Doctoral Fellows


Hao-Sen Chiang, Ph.D.
Lab Phone: 617-724-7564
Email: hchiang@partners.org


Song Liu, M.D.
Lab Phone: 617-724-7564
Email: sliu23@partners.org


Joo-Hye Song, Ph.D.
Lab Phone: 617-724-7564
Email: jsong6@partners.org


Yun Zhao, M.D. Ph.D.
Lab Phone: 617-724-7564
Email: yzhao11@partners.org



Past Trainees

Bayasi Guleng, PhD, Postdoctoral Research Fellow
Graduate School of Medicine, University of Tokyo
Current Position:  Professor of Medicine, Medical College of Xiamen University, Xiamen City, China

Carmen Alonso Cotoner, MD, Postdoctoral Research Fellow
Current Position: Faculty in Medicine, Institut de Recerca, Hospital Universitari Vall d’Hebron, Digestive Diseases Research Unit, Department of Gastroenterology, Barcelona, Spain

Sonal Gupta, MD, PhD, Postdoctoral Research Fellow
University of Bradford, United Kingdom

Seiji Arihiro, MD, PhD, Postdoctoral Research Fellow
Jikei University School of Medicine
Current position: Asst. in Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo, Japan

Atsuko Fukazawa, MD, Postdoctoral Research Fellow
Current position: Surgeon, Hamamatsu School of Medicine, Hamamatsu, Japan
Current position: Physician, Department of Internal Medicine,
Universitätsklinikum Ulm, Ulm, Germany

Mitsue Shimada MD, PhD, Postdoctoral Research Fellow
Current position: Physician, Department of Internal Medicine, Shiga Hospital, Japan

Kiyotaka Kurachi, MD, Postdoctoral Research Fellow
Current position: GI Surgeon, Hamamatsu School of Medicine, Japan
Takanori Sakaguchi, MD, PhD, Postdoctoral Research Fellow
Current position: Surgeon, Hamamatsu School of Medicine, Japan

Stephan Brand, MD, Postdoctoral Research Fellow
Current position: German Research Society, University Hospital Munich-Grosshadern, Department of Medicine II

Andreas Muellhofer, MD, Postdoctoral Research Fellow
Current position: Asst. in Medicine, Katharinehospital, Stuttgart, Germany

Kerstin Luedtke-Heckenkamp, MD, Postdoctoral Research Fellow
Current position: Asst. in Medicine, Kreiskrankenhaus, Marienhoehe, Abt. Geriatrie, Wuerselen, Germany

Tetsushi Kinugasa, MD, Postdoctoral Research Fellow
Current position: Asst. in Surgery, Fukuoka University School of Medicine, Japan

Pietro G. Andres, MD, Postdoctoral Research Fellow
Current Position: Senior Clinical Fellow in Gastroenterology, UC San Francisco, CA, HHMI Fellowship

Masaaki Awane, MD, Postdoctoral Research Fellow
Current position: Asst. in GI Surgery, Kyoto University Hospital, Japan

Raisuke Nishiyama, MD, Postdoctoral Research Fellow
Current position: Chief of GI surgery Hamamatsu-Kita Hospital, Japan

Unravel the genetic basis of Inflammatory Bowel Diseases (IBD)

The intestinal mucosa functions as an immunological organ, which plays a major role in the development of oral tolerance and the development of immunity. The defense response to microbiota in the lumen of the intestine is required to maintain health and to overcome disease. Crohn’s disease (CD) and ulcerative colitis (UC) are non-infectious, chronic and relapsing inflammatory diseases of the gastrointestinal tract characterized by injury to the barrier function of the intestine. This is the result of an exaggerated defense response to the intestinal microbiota leading to recurrent and long lasting episodes of diarrhea and abdominal pain. We study the function of newly discovered mediators of host defenses, which can regulate both inflammatory and inhibitory immune responses mediated by IBD-associated gene variants. The elucidation of the biology of these regulators will provide pivotal insights into the genetic basis of IBD. We aim to develop new insights into the reason for the enhanced immune responses and lack of their control in patients with inflammatory bowel diseases leading to chronic intestinal inflammation and delayed tissue repair.

Functional subspecifications of mucosal dendritic cells

Antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages are a diverse group of phagocytic cells that maintain tolerance and regulate adaptive immune responses. In the intestine, a combination of conventional DCs, migratory DCs and plasmacytoid-derived DCs form a surveillance system that is constantly engaged in sampling and processing of food antigens and commensal and pathogenic microbiota. This functional dichotomy poses unique challenges for the control of immune responses in the highly antigenic context of the intestine and the pivotal requirement to maintain intestinal barrier function. Consequently, DCs with distinct functional subspecifications have evolved in Peyer’s patches (PPs), mesenteric lymph nodes (MLNs) and the small intestine and colon in adaptation to different local environmental conditions However, the mechanism by which intestinal DCs control the mucosa specific adaptations of regulatory T cells (e.g., IL-10 secretion) and T helper cell function (e.g., induction of Th17 differentiation) is not well understood. Our studies will provide new insights into the region specific regulatory programs of DC systems in the large and small intestine for the control of adaptive immunity required for tissue repair in the highly antigenic environment of the intestine.

Signal transduction in innate immune regulation

These studies will provide new insights into the integration of innate immune activation pathways that are required for the recognition of microbiota at mucosal surfaces. In this project we directly address the mechanisms responsible for the recognition of microbial antigens and responses, which are a key area of importance for IBD research. Initial recognition of microbiota is mediated by pattern recognition receptors (PRRs) such as nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), Toll-like receptors (TLRs), Rik and MDA5 receptors, which recognize conserved microbial structures known as pathogen associated molecular patterns (PAMPs). The combination of these signaling pathways controls innate immune responses to microbial effectors, which include the activation of NF-κB dependent proinflammatory mediators such as TNF-α, but also initiates signaling circuitry stimulating IL-10 expression to control inflammation. The definition of the coordination of these different microbial recognition pathways is required for the understanding of innate immune responses at mucosal interphases where a multitude of antigenic information needs to be distinguished. These studies currently focus on a new component of pathogen recognition by caspase-recruiting domain (CARD)-containing NOD-like receptors. Defining the functional role of this newly discovered central component of microbial pattern recognition will provide pivotal insights into the mechanisms that disrupt mucosa specific control of innate immune responses required for mucosal inflammation as well as tissue repair in IBD.

Development of new therapeutics for intestinal inflammation

A more precise definition of the mechanisms of microbial recognition is required for the development of specifically targeted approaches for the control of IBD. None of the currently available treatments specifically target the reason for the disruption of inflammatory or inhibitory regulation underlying the diverse and multifactoral diseases, which we recognize as IBD. Based on newly identified regulatory circuits we are developing approaches to directly enhance inhibitory immune regulation to microbial factors without disrupting mucosal defenses.

Microbiome and host interactions in the intestine

Mucosal DCs form a major surveillance system in the lamina propria of the small and large intestine and are constantly engaged in sampling and processing of food antigens, commensal bacteria and intestinal pathogens. Antigens must cross the intestinal epithelium in a controlled manner and processed by DCs, since bacteria or their products are a primary risk factor for the development of intestinal inflammation. Dysregulation of this immune modulation in response to food antigens or bacterial recognition leads to intestinal inflammation in animal models of human inflammatory bowel diseases such as CD, US and celiac disease. In the context of the intestine, DCs can differentiate in an organ-specific fashion in response to a spectrum of environmental and endogenous stimuli. We unravel the molecular mechanisms that define the function of intestine specific DC subsets in the interaction with the intestinal microbiome.

Development of new functional imaging approaches for the mucosal immune system

In vivo visualization of biological processes including imaging of cellular membrane trafficking at a molecular level as well as clinical imaging of disease mechanisms in tissues in patients has become essential components of basic and clinical metabolic research. Non-invasive visible light imaging is now a widely accepted technology allowing researchers to follow many biological processes in healthy and diseased animal models. We utilize 3D and 4D analysis of bioluminescence, e.g., luciferase-based and fluorescence-based imaging to study the mucosal immune system in vivo and in vitro. Highly sensitive EM CCD cameras with signal enhancement provide quantitative real time imaging of cell migration and cell interaction during antigen presentation and membrane trafficking in immune cell of the intestine. We develop mouse model systems to apply live cell molecular imaging including, confocal, spinning disk confocal, Fret, Frap and TIRF microscopy for in vitro and in vivo imaging of cellular processes from the tracking and integration of dendritic cell precursors into intestinal tissues to the study of receptor uptake and signal transduction.

We are currently looking for Postdoctoral Fellows with an interest in signal transduction and mucosal immunology.

  1. Reinecker HC, Steffen M, Doehn C, Petersen J, Pfluger I, Voss A, Raedler A. Proinflammatory cytokines in intestinal mucosa. Immunol Res 1991;10:247-8.

     

  2. Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol 1993;94:174-81.

     

  3. Steffen M, Reinecker HC, Petersen J, Doehn C, Pfluger I, Voss A, Raedler A. Differences in cytokine secretion by intestinal mononuclear cells, peripheral blood monocytes and alveolar macrophages from HIV-infected patients. Clin Exp Immunol 1993;91:30-6.

     

  4. Reinecker HC, Loh EY, Ringler DJ, Mehta A, Rombeau JL, MacDermott RP. Monocyte-chemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosa. Gastroenterology 1995;108:40-50.

     

  5. Reinecker HC, Podolsky DK. Human intestinal epithelial cells express functional cytokine receptors sharing the common gamma c chain of the interleukin 2 receptor. Proc Natl Acad Sci U S A 1995;92:8353-7.

     

  6. Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK. Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 1996;111:1706-13.

     

  7. Rosenberg IM, Goke M, Kanai M, Reinecker HC, Podolsky DK. Epithelial cell kinase-B61: an autocrine loop modulating intestinal epithelial migration and barrier function. Am J Physiol 1997;273:G824-32.

     

  8. MacDermott RP, Sanderson IR, Reinecker HC. The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn's disease. Inflamm Bowel Dis 1998;4:54-67.

     

  9. Meijssen MA, Brandwein SL, Reinecker HC, Bhan AK, Podolsky DK. Alteration of gene expression by intestinal epithelial cells precedes colitis in interleukin-2-deficient mice. Am J Physiol 1998;274:G472-9.

     

  10. Awane M, Andres PG, Li DJ, Reinecker HC. NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol 1999;162:5337-44.

     

  11. Andres PG, Beck PL, Mizoguchi E, Mizoguchi A, Bhan AK, Dawson T, Kuziel WA, Maeda N, MacDermott RP, Podolsky DK, Reinecker HC. Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. J Immunol 2000;164:6303-12.

     

  12. Cario E, Rosenberg IM, Brandwein SL, Beck PL, Reinecker HC, Podolsky DK. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol 2000;164:966-72.

     

  13. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 2000;118:1001-11.

     

  14. Muehlhoefer A, Saubermann LJ, Gu X, Luedtke-Heckenkamp K, Xavier R, Blumberg RS, Podolsky DK, MacDermott RP, Reinecker HC. Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa. J Immunol 2000;164:3368-76.

     

  15. Nishiyama R, Sakaguchi T, Kinugasa T, Gu X, MacDermott RP, Podolsky DK, Reinecker HC. Interleukin-2 receptor beta subunit-dependent and -independent regulation of intestinal epithelial tight junctions. J Biol Chem 2001;276:35571-80.

     

  16. Sakaguchi T, Brand S, Reinecker HC. Mucosal barrier and immune mediators. Curr Opin Gastroenterol 2001;17:573-7.

     

  17. Brand S, Sakaguchi T, Gu X, Colgan SP, Reinecker HC. Fractalkine-mediated signals regulate cell-survival and immune-modulatory responses in intestinal epithelial cells. Gastroenterology 2002;122:166-77.

     

  18. Sakaguchi T, Gu X, Golden HM, Suh E, Rhoads DB, Reinecker HC. Cloning of the human claudin-2 5'-flanking region revealed a TATA-less promoter with conserved binding sites in mouse and human for caudal-related homeodomain proteins and hepatocyte nuclear factor-1alpha. J Biol Chem 2002;277:21361-70.

     

  19. Sakaguchi T, Kohler H, Gu X, McCormick BA, Reinecker HC. Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells. Cell Microbiol 2002;4:367-81.

     

  20. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 2003;124:993-1000.

     

  21. Mizoguchi E, Xavier RJ, Reinecker HC, Uchino H, Bhan AK, Podolsky DK, Mizoguchi A. Colonic epithelial functional phenotype varies with type and phase of experimental colitis. Gastroenterology 2003;125:148-61.

     

  22. Loser K, Mehling A, Apelt J, Stander S, Andres PG, Reinecker HC, Eing BR,
    Skryabin BV
    , Varga G, Schwarz T, Beissert S. Enhanced contact hypersensitivity and antiviral immune responses in vivo by keratinocyte-targeted overexpression of IL-15. Eur J Immunol 2004;34:2022-31.

     

  23. Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition. J Cell Biol 2005;170:21-6.

     

  24. Barnich N, Hisamatsu T, Aguirre JE, Xavier R, Reinecker HC, Podolsky DK. GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells. J Biol Chem 2005;280:19021-6.

     

  25. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 2005;307:254-8.

     

  26. Niess JH, Reinecker HC. Lamina propria dendritic cells in the physiology and pathology of the gastrointestinal tract. Curr Opin Gastroenterol 2005;21:687-91.

     

  27. Niess JH, Reinecker HC. Dendritic cells: the commanders-in-chief of mucosal immune defenses. Curr Opin Gastroenterol 2006;22:354-60.

     

  28. Niess JH, Reinecker HC. Dendritic cells in the recognition of intestinal microbiota. Cell Microbiol 2006;8:558-64.

     

  29. Salazar-Gonzalez RM, Niess JH, Zammit DJ, Ravindran R, Srinivasan A, Maxwell JR, Stoklasek T, Yadav R, Williams IR, Gu X, McCormick BA, Pazos MA, Vella AT, Lefrancois L, Reinecker HC, McSorley SJ. CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches. Immunity 2006;24:623-32.

     

  30. Higashi Y, Suzuki S, Sakaguchi T, Nakamura T, Baba S, Reinecker HC, Nakamura S, Konno H. Loss of claudin-1 expression correlates with malignancy of hepatocellular carcinoma. J Surg Res 2007;139:68-76.

     

  31. Kohler H, Sakaguchi T, Hurley BP, Kase BA, Reinecker HC, McCormick BA. Salmonella enterica serovar Typhimurium regulates intercellular junction proteins and facilitates transepithelial neutrophil and bacterial passage. Am J Physiol Gastrointest Liver Physiol 2007;293:G178-87.

     

  32. Fukazawa A, Alonso C, Kurachi K, Gupta S, Lesser CF, McCormick BA, Reinecker HC. GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors. PLoS Pathog 2008;4:e1000228.

     

  33. Seiderer J, Dambacher J, Leistner D, Tillack C, Glas J, Niess JH, Pfennig S, Jurgens M, Muller-Myhsok B, Goke B, Ochsenkuhn T, Lohse P, Reinecker HC, Brand S. Genotype-phenotype analysis of the CXCL16 p.Ala181Val polymorphism in inflammatory bowel disease. Clin Immunol 2008;127:49-55.

     

  34. Matharu KS, Mizoguchi E, Cotoner CA, Nguyen DD, Mingle B, Iweala OI, McBee ME, Stefka AT, Prioult G, Haigis KM, Bhan AK, Snapper SB, Murakami H, Schauer DB, Reinecker HC, Mizoguchi A, Nagler CR. Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10-deficient mice. Gastroenterology 2009;137:1380-90 e1-3.

     

  35. Ramasamy S, Nguyen DD, Eston MA, Nasrin Alam S, Moss AK, Ebrahimi F, Biswas B, Mostafa G, Chen KT, Kaliannan K, Yammine H, Narisawa S, Millan JL, Warren HS, Hohmann EL, Mizoguchi E, Reinecker HC, Bhan AK, Snapper SB, Malo MS, Hodin RA. Intestinal alkaline phosphatase has beneficial effects in mouse models of chronic colitis. Inflamm Bowel Dis 2010.

     

  36. Diegelmann J, Seiderer J, Niess JH, Haller D, Goke B, Reinecker HC, Brand S. Expression and regulation of the chemokine CXCL16 in Crohn's disease and models of intestinal inflammation. Inflamm Bowel Dis. 2010 May 10. [Epub ahead of print] PMID: 20848509

     

  37. Hang L, Setiawan T, Blum AM, Urban J, Stoyanoff K, Arihiro S, Reinecker HC, Weinstock JV. Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity.  J Immunol. 2010 Sep 15;185(6):3184-9. Epub 2010 Aug 11. PMID:20702728 [Pubmed - in process]

     

  38. Berger SB, Romero X, Ma C, Wang G, Faubion WA, Liao G, Compeer E, Keszei M, Rameh L, Wang N, Boes M, Regueiro JR, Reinecker HC, Terhorst C. SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages. Nat Immunol. 2010 Oct;11(10):920-7. PMID:20818396 [PubMed - in process]

     

  39. Sidhu M, Alonso Cotoner C, Guleng B, Arihiro S, Chang S, Duncan K W, Ajami AM, Chau M, Reinecker HC. Small Molecule Tyrosine Kinase Inhibitors for the Treatment of Intestinal Inflammation. Inflamm Bowel Dis. 2011, accepted for Publication.

     

  40. Da Silva N, Cortez-Retamozo V, Reinecker HC, Wildgruber M, Hill E, Brown D, Swirski F, Pittet M, Breton S. A dense network of dendritic cells populates the murine epididymis.  Reproduction. 2011 Feb 10. [Epub ahead of print]

     

  41. Wang S, Villablanca EJ, De Calisto J, Gomes DC, Nguyen DD, Mizoguchi E, Kagan JC, Reinecker HC, Hacohen N, Nagler C, Xavier RJ, Rossi-Bergmann B, Chen YB, Blomhoff R, Snapper SB, Mora JR. MyD88-Dependent TLR1/2 Signals Educate Dendritic Cells with Gut-Specific Imprinting Properties. J Immunol. 2011 Jul 1;187(1):141-50. Epub 2011 Jun 6.

     

  42. Yun Zhao, Carmen Alonso 2, Isabel Ballester Ph.D, Joo Hye Song, Sun Young Chang, Bayasi Guleng, Seiji Arihiro, Peter J. Murray, Ramnik Xavier, Koichi S. Kobayashi and Reinecker HC. Control of NOD2- and Rip2-Dependent Innate Immune Activation by GEF-H1. Inflamm Bowel Dis. 2011 accepted for publication.

     

  43. Nagatani K, Wang S, Llado V, Lau CW, Li Z, Mizoguchi A, Nagler CR, Shibata Y, Reinecker HC, Mora JR, Mizoguchi E. Chitin microparticles for the control of intestinal inflammation.Inflamm Bowel Dis. 2012