For a new therapy of Crohn's disease using chronic colitis model in mice.

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The patients with Crohn's disease have increased in Japan, but its pathogenesis has not yet been clarified.Recently, Th-1 helper T cells have been reported to play important roles on the development and exacerbation of Crohn's disease in human.Some chemicals such as TNBS and DSS bye been shown to induce chronic colitis in Rat.Especially, it is reported that TNBS-induced colitis resembles to human Crohn's disease.Therefore, we planned to develope chronic colitis model in mice, to make use of for the developemnet of a new therapeutic tool for the patients with Crohn's disease.First, we tried to develope chronic colitis model in mice by TNBS enema, in the same method as that used for rat.However, we could not succeed in the developement of chronic colitis in mice, instead of several species of mouse and several administration doses of TNBS.Next, we selected wasting disease model with diarrhea and colitis in mice.This model, which is introduced by administration of CD4^+CD45RB^<high> T cel … More ls, is known to show Th-1 cell mediated colitis in mice.After sorting CD4^+CD45RB^<high> T cells from splenic lymphocytes using magnet bead and FACS, a fraction of CD4^+CD45RB^<high> T cells was injected intraperitoneally into Balb/c SCID mouse.Diarrhea appeared about 3-4 weeks after injection and body weight decreased gradually to the level of 10% below before injection in about 8 weeks, in comparison to the increase of body weight in control mice.Histological examination revealed mucosal hyperpiasia, goblet cell depression and mononuclear cell infiltration in intestinal mucosa.The expression of IFN-gamma and IL-6 mRNA in the mucosa was significantly elevated.Thus, we tried to elucidate the effect of anti-mouse IL-6 receptor monoclonal antibody (aIL6RmAb) on the colitis and body weight loss in this chronic colitis model In mice.Interestingly, aIL6RmAb prevented the appearance of diarrhea and body weigt loss in mice introduced by CD4^+CD45RB^<high> T cells, by the administration of aIL6RmAb (1mg/mouse) intraperitoneally weekly since the injection of CD4^+CD45RB^<high> T cells.The aIL6RmAb prevented the mucosal hyperplasia and inflammation and also inhibited the expressoin of IFN-gamma in the mucosa.These results suggest that aIL6RmAb may become a useful therapeutic tool for the patients with Crohn's disease.Further examination of the effect of aIL6RmAb after the occurrence of colitis in mice injected CD4^+CD45RB^<high> T cells will be needed for its application to the patients with Crohn's disease. Less