Inflammatory bowel disease (IBD), including Crohn's Disease and ulcerative colitis (UC), is a lifelong T cell- mediated inflammatory condition of the small intestine or colon. The highly proinflammatory cytokine interleukin-17 (IL-17) is elevated in proportion to disease activity in intestinal biopsies of both Crohn's and UC patients but is virtually absent in unaffected individuals. A new class of effector CD4+ T cells, known as Th-17 cells, has recently been identified that expresses IL-17 and several other inflammatory cytokines. The Th-17 cell is distinct from the better-studied Th1 and Th2 effector T cells and is the major T cell lineage implicated in animal models of colitis and other types of autoimmune disease. The applicants have identified structurally diverse small molecule antagonists to a previously unexplored orphan receptor that is required for CD4+ Th-17 cell differentiation. In cell culture, these receptor antagonists block Th-17 cell formation from na?ve CD4+ T cells, inhibit the expansion of memory Th-17 cells following challenge by antigen, and suppress IL-17 release. These findings suggest that an orally bioavailable small molecule antagonist will have significant therapeutic potential in the treatment of IBD. This proposed new small molecule therapeutic class will also have significant therapeutic advantages--such as oral bioavailability and greater ease of administration--over injectable monoclonal antibodies to key cytokines in the Th-17 pathway such as IL-17 and IL-23.
The specific aims of this proposal are to: (1) demonstrate that the novel receptor antagonists block IL-17 release in isolated intestinal tissue as expected if suppression of intestinal Th-17 is a target of the new compound class; (2) synthesize and characterize small molecule lead antagonists for in vivo studies from antagonists already identified at Orphagen; and (3) investigate lead antagonist suppression of disease activity in an established model of murine colitis that reflects Th-17 activity and is induced by transfer of na?ve CD4+CD45RBhigh T cells to immunocompromised mice. Leads identified in this study will facilitate the identification of potential clinical candidates for treatment of IBD and other autoimmune indications in planned Phase II research.
Crohn's disease and ulcerative colitis are chronic, intestinal disorders for which treatment options are limited. The side effects of current medications are significant. We propose to characterize and develop a novel class of small molecule drugs that suppresses the formation and function of a novel lineage of T cells that appear to have a central role in the immune pathology of the disease. ? ? ?