| 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 |
