GUT FLORA AS A PROVOCATEUR OF AUTOIMMUNE COLITIS

描述：(改编自申请人的摘要)：这一目标 研究建议利用白介素2缺乏(IL-2-/-) 小鼠作为溃疡性结肠炎(UC)动物模型的确定作用 肠道细菌在炎症性肠炎发病机制中的作用 疾病(IBD)。关于IBD发病的一个长期假说是 宿主遭受正常维持的机制的故障 对肠道环境抗原的“口服耐受性”，例如 共生细菌。这种不规范的原因和其他原因一样不清楚。 大多数正常运行的机制是为了维持 对肠道共生菌反应迟钝。然而，IL-2/-小鼠， 似乎提供了一个很有前途的模型来探索可能的关系 肠道细菌抗原和可能启动的特定T细胞之间 炎症性肠病损。已知这些小鼠会发展成致病 许多组织中的突起，包括与所见病变相似的IBD病变 在UC患者中，这些变化被推迟或通过维持 小鼠处于特定的无病原体或无细菌的条件下。使用这些 小鼠的PI建议确定是否内源性抗原识别 黏膜T细胞所产生的微生物菌群可引发或维持IBD。 这些研究的指导性假设是炎性免疫 IL-2-小鼠的反应和结肠炎是导致 调节T细胞对正常肠道菌群的反应。白介素2 因此，可能需要生成和/或运行 调节性群体(S)的粘膜T细胞或，直接参与 抑制对肠道抗原的炎症反应的发展。 PI建议的研究，以实验验证这一假设使用 IL-2-\-小鼠有两个特定的目的。第一个是确定成员 能激活粘膜T细胞的共生肠道细菌 结肠炎。第二个目标是调查相互作用的性质 结肠上皮细胞和粘膜T细胞之间的关系及T细胞如何 调节上皮细胞损伤，这是结肠炎的一个显著特征。 特别是，上皮细胞可以调节粘膜的可能性 T细胞作为抗原提呈物对肠道抗原的反应 细胞，并通过产生可溶性生长因子的粘膜 T细胞可以影响上皮细胞的生长和功能 调查过了。此外，致病T细胞引起或 通过产生有毒或炎性物质来促进组织损伤 细胞因子也将被调查。

DESCRIPTION: (Adapted from the applicant's abstract): The goal of this research proposal is to utilize the Interleukin-2-deficient (IL-2-/-) mouse as an animal model of ulcerative colitis (UC) to determine the role commensal gut bacteria play in the pathogenesis of inflammatory bowl disease (IBD). A perennial hypothesis for the initiation of IBD is that the host suffers a breakdown in the mechanisms that normally maintain "oral tolerance" against environmental antigens in the gut such as commensal bacteria. The cause of this disregulation is obscure, as are most of the mechanisms that normally operate to maintain hyporesponsiveness to gut commensal bacteria. The IL-2/- mouse, however, seems to offer a promising model to probe the possible relationships between gut bacterial antigens and specific T cells that may initiate inflammatory bowl lesions. It is known that these mice develop pathogenic processes in many tissues, including IBD lesions that resemble those seen in UC patients, and that these are postponed or moderated by maintaining the mice under specific pathogen-free or germ-free conditions. Using these mice the PI proposes to determine if antigen recognition of endogenous microbial flora by mucosal T cells can initiate or maintain IBD. The guiding hypothesis for these studies is that the inflammatory immune response and colitis in IL-2-\- mice is a consequence for the loss of regulation of T cell responses to normal intestinal bacterial flora. IL-2 may, therefore, be required for the generation and\or function of a regulatory population(s) of mucosal T cells or, be directly involved in inhibiting the development of inflammatory responses to enteric antigens. The PI's proposed studies to experimentally test this hypothesis using the IL-2-\- mice have two specific aims. The first is to identify members of commensal enteric bacteria that can activate mucosal T cells that initiate colitis. The second aim is to investigate the nature of the interaction between colonic epithelial cells and mucosal T cells and how T cells mediate the epithelial cell injury that is a hallmark feature of colitis. In particular, the possibility that epithelial cells can regulate mucosal T cell responses to enteric antigens by functioning as antigen presenting cells, and that through the production of soluble growth factors mucosal T cells can influence epithelial cell growth and function will be investigated. In addition, the ability of pathogenic T cells to cause or promote tissue injury through the production of toxic or inflammatory cytokines will also be investigated.