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

使用小鼠慢性结肠炎模型开发克罗恩病的新疗法。

基本信息

批准号：
09670545
负责人：
NAKAMURA Hideji
金额：
$ 1.66万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670545/
关键词：
I.B.D.Crohn's Disease chronic colitis model

项目摘要

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

近年来，Th-1辅助性T细胞在人类克罗恩病的发生发展中起着重要的作用。一些化学物质如TNBS和DSS BYE被证明可以诱发大鼠慢性结肠炎。特别是有报道称，TNBS诱导的结肠炎与人类克罗恩病相似。因此，我们计划建立小鼠慢性结肠炎模型，为克罗恩病患者开发一种新的治疗工具。首先，我们尝试通过TNBS灌肠，建立小鼠慢性结肠炎模型，方法与大鼠相同，但不能成功地复制小鼠慢性结肠炎模型，而不是用几种小鼠和几种剂量的TNBS。高性能…用磁珠和流式细胞仪从小鼠脾淋巴细胞中分离出一小部分Th-1细胞介导的结肠炎。将T细胞注射到Balb/c SCID小鼠体内。注射后3-4周出现腹泻，8周左右体重逐渐下降到注射前的10%以下。组织学检查显示粘膜肥大，杯状细胞抑制，肠粘膜中单个核细胞浸润。黏膜中干扰素-γ和IL-6mRNA的表达显著上调。因此，我们试图阐明抗小鼠IL-6受体单抗(AIL6RmAb)对小鼠慢性结肠炎和体重减轻的作用AIL6RmAb可预防CD4^+CD45Rb^&lt诱导的小鼠腹泻和体重丢失；AIL6RmAb(1 mg/只)给小鼠注射CD4RmAb(1 mg/只)后，每周一次给小鼠腹腔注射aIL6RmAb(1 mg/只)。aIL6RmAb可预防黏膜增生和炎症，并抑制黏膜中干扰素-γ的表达。提示aIL6RmAb可能成为克罗恩病患者的有效治疗工具。进一步观察aIL6RmAb对注射CD45Rb+CD45Rb；高GT；T细胞的小鼠结肠炎的治疗作用。较少