The role of CD1d in the regulation of mucosal inflammation
07 / 2007 - unknown
Inflammatory bowel disease (IBD), Crohn s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract. The hypothesis on the pathogenesis is that IBD results from aberrant mucosal immune responses to intestinal commensal bacteria. Although detrimental T-cell responses are implicated, to date no specific disease associated T-cell antigens or specific pathogenic T-cells have been identified.Previously, we have shown that the class-I type lipid-antigen presenting molecule CD1d and CD1d restricted NKT-cells contribute to a murine model for UC. These findings have been extended to human disease by showing that the atypical Th2 response in UC is mounted by lamina propria NKT-cells. Earlier studies in another colitis-model however, suggested that NKT-cells can, in contrast, protect from colitis. Given the role of the microbiota in IBD, we studied the potential role for NKT-cells in microbial homeostasis. Recently, we have established that CD1d and CD1d restricted NKT-cells regulate colonization of the intestine with gram-negative and gram-positive bacteria. This pathway involves Paneth cells (Pc), that are crypt cells of the small intestine. Pc provide host defense against micro-organisms through the secretion of various of antimicrobial molecules.Hypothesis:NKT-cells recognize lipid-antigens induced by and/or associated with luminal bacteria. In homeostasis (health), colonizing bacteria activate NKT-cells that regulate Pc function, resulting in the control of bacterial colonization and protection from colitis. Pathogenic or inadequate CD1d-NKT activation contributes to colitis (IBD), directly through cytotoxic cytokine production or indirectly through decreased Pc function resulting in an enhanced bacterial burden.Overall AIM:To determine the contributions of the CD1d-NKT-microbiota axis to the IBD pathogenesis.Specific AIMS:I: Identification of microbial or endogenous lipid-antigen responsive NKT-cells in murine colitis and IBD patientsII: Exploring the working mechanisms of NKT-cell regulated colonization by intestinal microbiotaIII: Identification of IBD-associated microbiota that specifically trigger the CD1d-NKT-Pc pathway
In de darm heerst vrede tussen afweersysteem en bacteriën. Bij verstoring van dit evenwicht kan chronische darmontsteking ontstaan. De onderzoekers brengen darmbacteriën in aanraking met verschillende afweercellen van gezonde mensen en patiënten. Bestudeerd wordt hoe deze twee op elkaar reageren.