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DELETION OF CD47 PROTECTS FROM MURINE EXPERIMENTAL CROHN’S DISEASE
G Fortin, M Raymond, M Rubio, M Sarfati, D Franchimont
A recent change in the paradigm regarding the pathogenesis of Crohn’s disease revealed that IL-23 is instrumental in promoting the expansion of IL-17-producing T cells (Th17). Indeed, the recently demonstrated mutation in the human IL-23 receptor gene is protective in the development of Crohn’s disease. In addition, the IL-17 receptor is essential for the development of trinitrobenzene sulfonic acid (TNBS) colitis. BALB/c CD47 –/– mice display a Th1 biased phenotype, as evidenced by an increased production of IL-12 and IFNgamma, two cytokines described as inhibitory in the differentiation of Th17 cells . This Th1 phenotype, in combination with a defect in neutrophil and dendritic cell migration, led us to postulate that a deficiency in CD47 would be protective in the development of TNBS colitis. In this study, acute or chronic TNBS colitis was induced in wild type and CD47 –/– mice, and the latter were found to be less susceptible to developing acute (day 2 and day 4) colitis, and were resistant to chronic (reactivation after 7 days) colitis. This protection was observed at the systemic (weight loss and serum cytokines) and local (macroscopic and microscopic score, and colon cytokine mRNA) level. A significant reduction of IL-23, TGFbeta, IL-6 and IL-17 mRNA expression in the colons of CD47 –/– mice was correlated with the protection conferred by the lack of CD47. We conclude that deletion of CD47 is protective in the development of intestinal inflammation. Pharmaceutical neutralization of CD47 may therefore prove beneficial in the treatment of human Crohn’s disease.
Supported by the Crohn’s and Colitis Foundation of Canada (CCFC) Grant # 3801