GUT FLORA AS A PROVOCATEUR OF AUTOIMMUNE COLITIS

描述：（改编自申请人的摘要）：本文的目标 研究建议是利用白细胞介素-2-缺陷（IL-2-/-） 小鼠作为溃疡性结肠炎（UC）的动物模型，以确定其作用 肠道细菌在炎症性肠病发病机制中的作用 疾病（IBD）。IBD发病的长期假设是， 宿主的正常维持机制就会崩溃 针对肠道中的环境抗原的“口服耐受性”， 肠道细菌。这种失调的原因是模糊的，因为 大多数通常用来维持 对肠道细菌的低反应性。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 肠道细菌抗原和特异性T细胞之间的联系， 炎症性肠病变。据了解，这些小鼠会产生致病性 许多组织中的病变，包括与所见病变相似的IBD病变 在UC患者中，通过维持 小鼠在特定的无病原体或无菌条件下。使用这些 PI建议确定小鼠内源性抗原识别 通过粘膜T细胞的微生物植物群可以启动或维持IBD。 这些研究的指导假设是，炎症免疫 IL-2-小鼠中的免疫应答和结肠炎是IL-2-小鼠中的免疫应答丧失的结果。 调节T细胞对正常肠道细菌植物群的应答。IL-2 因此，可能需要产生和/或功能， 粘膜T细胞的调节群体，或直接参与 抑制对肠抗原的炎症反应的发展。 PI提出的研究旨在使用以下方法对这一假设进行实验性检验： IL-2-小鼠有两个特定的目标。第一，确定成员 肠道细菌可以激活粘膜T细胞， 结肠炎第二个目的是研究相互作用的性质 结肠上皮细胞和粘膜T细胞之间的联系， 介导上皮细胞损伤，这是结肠炎的标志性特征。 特别是，上皮细胞可以调节粘膜的可能性， T细胞对肠道抗原的抗原递呈应答 细胞，并通过生产可溶性生长因子粘膜 T细胞可以影响上皮细胞的生长和功能， 研究了此外，致病性T细胞引起或 通过产生毒性或炎性物质促进组织损伤 还将研究细胞因子。

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.