Development of novel therapy targeting innate immunity for Crohn's disease

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Crohn's disease (CD) is a chronic inflammatory process involving the gastrointestinal tract, characterized by discontinuous and transmural inflammation. Although the etiology of CD is not fully understood, accumulating evidence suggests that dysregulation of the local immune system is pivotal in the pathogenesis of CD. Studies from humans and experimental murine colitis models indicate that in CD, the local immune response tends to be predominantly T helper cell type 1 (Th1) and is reflected by local release of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-12, and IL-18. However, it has not been elucidated what triggers the Th1 immune response in CD. In the present study, we attempted to establish the purification of dendritic cells from mesenteric lymph nodes (MLN) and to analyze the immune cascade in the mesenteric lymph nodes of human CD.We established the purification of dendritic cells from MLN by density gradient centrifugation and immunomagnetic depletion of CD3^+,CD11b^+ and CD16^+cells followed by positive isolation with CD4^+. The analysis of cells obtained from MLNs revealed that the proportion of DC1 was increased in the MLN of CD compared to ulcerative colitis and control and that CD4+ T lymphocytes from the MLN of CD show a Th1 profile.Furthermore, we tried to elucidate the roles of macrophages in intestinal inflammation by using an IL-10-deficient (IL-10-/-) mouse colitis model, and demonstrated that abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. These data provide new insights into the intestinal macrophages to gut flora relationship in the development of colitis in IL-10-/- mice.