Die Bedeutung der Migration von Zellen des angeborenen Immunsystems für die Entscheidung zwischen entzündlicher und tolerogener Immunantwort im Darmtrakt
Zusammenfassung der Projektergebnisse
Initiating and perpetuating inflammation as well as resolution of inflammation and tolerance induction is dependent on directed migration of immune cells. Homing patterns are controlled by the expression of chemokines and adhesion molecules in the target tissue which specifically recruits lymphocyte subsets expressing the appropriate receptors. Interactions of the adhesion molecules α4β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) direct lymphocytes to the intestine and inflammation of the intestine is associated with an enhanced expression of MAdCAM-1 and an increased density of α4β7 integrin positive cells. Preventing leukocyte recruitment to inflammatory sites by selectively interfering with leukocyte-endothelial interactions represents a promising strategy for IBD treatment and antibodies targeting α4β7 integrin or MAdCAM-1 are effective in treating IBD. However the exact mechanisms of action and types of immune cells targeted by these anti-adhesion therapies have not been defined sufficiently. To answer these questions, we performed a detailed analysis of the MAdCAM-1 or β7 integrindependent migration of different subsets of innate immune cells to the critical sites of intestinal immune regulation under homeostatic conditions. Thereby we could demonstrate that MAdCAM-1/β7 integrin interactions are important for the localization of conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) in the intraepithelial compartment of the small intestine. MAdCAM-1 mediates the migration of pDC and DC precursors from the bone marrow via the circulation into the intraepithelial compartment. In addition, we were able to demonstrate that the migration of activated cDCs from the small intestine to the mesenteric lymph nodes is MAdCAM-1 independent. Moreover, we investigated the role of β7 integrin-MAdCAM-1 interactions for the migration of specific subsets of innate immune cells in the pathogenesis of IBD. Hereby we could show that beyond its role in lymphocyte trafficking, β7 integrin exacerbates colitis by promoting the accumulation of effector monocytes within the inflamed intestine, most probably mediated via interaction with MAdCAM- 1. Thus our study contributed to a better understanding of the cell migration pathways associated with the pathogenesis of experimental colitis and identified inflammatory monocytes as a potential target for specific anti-adhesive drugs. Moreover, concerning the role of β7 integrin-MAdCAM-1 interactions for the development of oral tolerance, we could demonstrate that immunogenic as well as tolerogenic humoral immune responses established in the gut are dependent on β7 integrin. Our studies indicate that expression of β7 integrin on innate immune cells is critically involved in the development of oral B cell tolerance. These findings extended our understanding of the process of oral tolerance induction and may have implications for oral vaccine development or oral immunotherapy against allergy. Particularly immunotherapies blocking β7 integrin receptors during chronic intestinal inflammation could have the potential to interfere with normal tolerogenic mechanisms in the gastrointestinal mucosa.
Projektbezogene Publikationen (Auswahl)
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(2011). Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34:237-246
Hadis, U., Wahl, B., Schulz, O., Hardtke-Wolenski, M., Schippers, A., Wagner, N., Müller, W., Sparwasser, T., Förster, R., Pabst, O.
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(2012). β7 integrin controls immunogenic and tolerogenic mucosal B cell responses. Clin. Immunol. 144:87-97
Schippers, A., Kochut, A., Pabst, O., Frischmann, U., Clahsen, T., Tenbrock, K., Müller, W., Wagner, N.
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(2014). Localization of dendritic cells in the gut epithelium requires MAdCAM-1. Clin. Immunol. 2015:74-84
Clahsen, T., Pabst, O., Tenbrock, K., Schippers, A., Wagner, N.
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(2015). Active suppression of intestinal CD4+TCT+T-lymphocyte maturation during the postnatal period. Nat. Commun. 6:7725
Torow, N., Yu, K., Hassani, K., Freitag, J., Schulz, O., Basic, M., Brennecke, A., Sparwasser, T., Wagner, N., Bleich, A., Lochner, M., Weiss, S., Förster, R., Pabst, O., & Hornef, M.W.
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(2015). Differential effects of gut-homing molecules CC chemokine receptor 9 and integrin-beta7 during acute GvHD of the liver. Biol. Blood Marrow Transplant. 21:2069-2078
Schreder A., Moschovakis, G.L., Halle, S., Schlue, J., Lee, C.W., Schippers, A., David, S., Bernhardt, G., Ganser A., Pabst, O., Förster, R., Koennecke, C.
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(2015). β7 integrin controls enterocyte migration in the small intestine. World J. Gastroenterol. 21:1759-1754
Kaemmerer, E., Kuhn, P., Schneider, U., Clahsen, T., Jeon, M.K., Klaus, C., Andruszkow, J., Härer, M., Ernst, S., Schippers, A., Wagner N., Gassler, N.
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(2015). β7 integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon. Mucosal Immunol. 9: 527-538
Schippers, A., Muschaweck, M., Clahsen, T., Tautorat, S., Grieb, L., Tenbrock, K., Gaßler, N., Wagner, N.
