Inflammatory bowel diseases (IBD) are the result of complex interactions between susceptibility and severity genes, the environment and the mucosal immune system. These interactions lead to an exaggerated mucosal immune response to constituents of the commensal flora. With the advent of high-throughput molecular technologies, several genome wide association studies (GWAS) have begun to define critical molecules and pathways that converge in physiologic processes that lead to mucosal inflammation. This technique can also be used to focus in vivo mouse studies for eventual development of targeted therapeutics for defined subsets of Crohn's disease (CD) patients. Tumor necrosis factor superfamily member 15 (TNFSF15) is the only one of the several recently discovered CD associated genes that is present in all ethnic groups. The product of the TNFSF15 gene, TL1A, has been defined as a master regulatory protein that plays a key role in human intestinal inflammation. Recent studies have also defined a critical role for TL1A in the pathogenesis of mouse experimental autoimmune encephalomyelitis (EAE), models of allergic lung inflammation and human rheumatoid arthritis. During the last grant cycle, we have generated a large body of data showing the importance of TL1A in human CD. We determined that TL1A is elevated in lamina propria mononuclear cells from the mucosa of patients with CD but the level varies among individual patients with similar amounts of inflammation. GWAS established that TNFSF15 is a CD susceptibility/severity gene. We demonstrated that antibodies to TL1A prevented and treated chronic colitis by decreasing Th1 and Th17 responses in two T cell mediated mouse models, confirming a role for TL1A in severity of inflammation. Finally, we found that the level TL1A protein expression varies in association with different CD genotypes, as defined by ethnic background, haplotype and serum antibody responses. Our hypothesis is that myeloid (antigen presenting cell, APC) generation of TL1A is a dominant event that determines the severity of chronic intestinal inflammation by enhancing intestinal Th1 and Th17 responses, leading to exacerbated inflammation in CD. Further elucidation of the in vivo cellular and molecular mechanisms of TL1A function in mucosal inflammation, the mechanisms of optimal bacterial induction of TL1A, and the relationship of genetic variation in the TNFSF15 gene to maximal ligand induced TL1A protein expression will help us to identify subsets of CD patients most likely to benefit from therapeutic inhibition of TL1A function. The following Specific Aims will test this hypothesis.1) Determine the in vivo role of myeloid v. T cell expression of TL1A in the development and severity of chronic colitis in the mouse. 2) Determine the roles of endocytosis and autophagy in the bacterial induction of maximal TL1A expression in human and murine (myeloid) APC. 3) Determine the relationship between variants in the CD associated TNFSF15 gene and the level of expression of TL1A mRNA and protein in human myeloid cell populations.
Inflammatory bowel diseases (IBD) affects more than 1,000,000 Americans. The studies of the role of Tumor necrosis factor superfamily member 15 (TNFSF15, TL1A) in severity of inflammation in Crohn's disease potentially could lead to the development of targeted therapeutics for a defined patient subpopulation.
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