Identifying new therapeutic targets for the treatment of Crohn's disease: The role of CD47 and L-carnitine in the pathogenesis and treatment of a murine model of intestinal inflammation.

摘要

Crohn's disease (CD) is a chronic, relapsing and remitting immune-mediated inflammatory disease of the gastrointestinal tract. While there is currently no cure for this disease, a wide range of treatment options are available. However, these are often associated with a significant set of adverse effects and, despite their use, most CD patients will eventually require hospitalization and/or surgery. The goal of the projects outlined in this thesis was therefore to further our understanding of the mechanisms involved in generating intestinal inflammation and to apply these findings to develop novel therapeutic agents.;L-carnitine is an amino acid derivative normally present in meat and dairy products and is also available as an over-the-counter nutritional supplement. Since mutations in the L-carnitine transporters, OCTN1 and OCTN2, were found to be associated with CD, we sought to examine its role in the development of intestinal inflammation. Remarkably, L-carnitine displayed immunosuppressive properties both in vitro and in vivo, effectively suppressing both the innate and the adaptive arms of the immune response and resulting in a significant reduction in the development of intestinal inflammation.;We have thus identified CD47 as an important regulator of SIRPalpha + DC trafficking, and demonstrate that this DC subset is implicated in the development of intestinal inflammation. Additionally, we have identified two promising new therapeutic candidates, CD47-fc and L-carnitine, for the treatment of CD.;We first examined the role of interactions between CD47 and its ligand, signal regulatory protein alpha (SIRPalpha), in the development of TNBS colitis, a murine model of intestinal inflammation sharing many features with human CD. We have demonstrated that dendritic cells (DC) expressing SIRPalpha promote Th17 responses and the development of experimental colitis. Furthermore, we identify an important role for CD47 in the migration of SIRPalpha + DCs to the lamina propria and mesenteric lymph nodes, where they participate in inducing inflammation. Thus, by genetic deletion of CD47 or by impairing its function using a CD47-fc fusion molecule, we have successfully reduced the severity of intestinal inflammation.