GUT FLORA AS A PROVOCATEUR OF AUTOIMMUNE COLITIS

肠道菌群是自身免疫性结肠炎的诱发因素

• 批准号: 2887495
• 负责人: Peter J Felsburg
• 金额: $ 19.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887495
• 关键词: T lymphocyte; autoimmune disorder; bacterial antigens; bacterial cytopathogenic effect; cell mediated lymphocytolysis test; cytokine; disease /disorder model; enteric bacteria; gastrointestinal epithelium; inflammatory bowel diseases; interleukin 2; intestinal mucosa; laboratory mouse; mucosal immunity; pathologic process; tissue /cell culture; ulcerative colitis

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.

描述：（改编自申请人的摘要）：本项目的目标 研究计划是利用白介素 2 缺陷 (IL-2-/-) 小鼠作为溃疡性结肠炎（UC）动物模型的作用确定 共生肠道细菌在炎症碗的发病机制中发挥作用 疾病（炎症性肠病）。 IBD 起始的一个长期假设是 宿主的正常维持机制出现故障 针对肠道环境抗原的“口服耐受性”，例如 共生细菌。这种失控的原因尚不清楚，因为 大多数正常运作的机制是为了维持 对肠道共生细菌的反应低下。然而，IL-2/-小鼠， 似乎提供了一个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 炎症碗病变。众所周知，这些小鼠会产生致病性 许多组织中的过程，包括类似于所见的 IBD 病变 在 UC 患者中，并且这些可以通过维持来推迟或缓和 将小鼠置于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是否 粘膜 T 细胞的微生物菌群可以引发或维持 IBD。 这些研究的指导性假设是炎症免疫 IL-2-\- 小鼠的反应和结肠炎是丧失 调节 T 细胞对正常肠道细菌菌群的反应。白细胞介素2 因此，可能需要一个 粘膜 T 细胞的调节群体，或直接参与 抑制肠道抗原炎症反应的发展。 PI 提出的研究使用以下方法通过实验检验这一假设： IL-2-\- 小鼠有两个具体目标。首先是确定成员 肠道共生细菌可以激活粘膜 T 细胞，从而启动 结肠炎。第二个目标是研究相互作用的本质 结肠上皮细胞和粘膜 T 细胞之间以及 T 细胞如何 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 细胞通过发挥抗原呈递作用对肠抗原作出反应 细胞，并通过粘膜产生可溶性生长因子 T细胞可以影响上皮细胞的生长和功能 调查了。此外，致病性 T 细胞能够引起或 通过产生毒性或炎症促进组织损伤 细胞因子也将被研究。