The Pathogenesis Of Colitis In A Novel Th2 Model Of IBD

描述(由申请人提供)：本项目的总体目标是 为了进一步了解粘膜免疫系统及其缺陷 与人类炎症性肠病(IBD)的发病机制有关。这个 IBD小鼠模型的建立为研究提供了便利 探讨IBD发病的基本机制。尽管事实是 大多数IBD小鼠模型是由已知的单一蛋白缺陷引起的 影响白细胞功能的特定自身反应或调节细胞 负责疾病发病机制的人群仍不清楚。这个 Wiskott-Aldrich综合征是几种免疫缺陷之一 与自身免疫有关，包括IBD。我们最近生成了一个 靶向干扰IBD的小鼠模型 Wiskott-Aldrich综合征蛋白(WASP)。黄蜂仅在 是一种调节细胞表面的信号分子 受体向细胞骨架发出信号。这种蛋白质的异常会导致 以它的名字命名的罕见的X连锁原发免疫缺陷。大多数人 黄蜂KO(WKO)小鼠也会患结肠炎。我们的初步研究表明 WKO小鼠的结肠炎是独一无二的，可能更类似于人类IBD，而不是 其他IBD小鼠模型，因为WASP缺乏不会导致丢失 特定的T细胞类别(例如，α-βT细胞)或不存在 特定的细胞因子(如IL-2、IL-10)对每个造血细胞的发育起作用 血统是完整的，尽管WASP调节肌动蛋白细胞骨架的事实 在所有的造血细胞中。与大多数IBD小鼠模型相比， 有Th1偏向，我们证明了从结肠分离的淋巴细胞 WKO小鼠固有层分泌Th2细胞因子模式。此外，我们的 遗传和收养转移研究已经确定了以下要求 淋巴细胞在疾病发病机制中的作用及CD4T细胞的特异性 传播性疾病。此外，WKO小鼠的调节性T细胞减少 已知可以调节小鼠的自身免疫力。初步数据还表明， 微生物在疾病的发病机制中起着至关重要的作用。有趣的是， 非致命性照射导致结肠炎严重程度显著增加 拥有100%的疾病渗透率。我们的第一个目标是定义 黄蜂在调节和效应T细胞功能中的作用 IBD的启动和维持过程中的额外白细胞群。我们的第二个 目的是确定Th2细胞因子的需求和炎症的作用 和抑制细胞因子在结肠炎发展中的作用。我们的最终目标是 建议评估细菌和屏障功能在结肠炎中的作用 在WKO小鼠中的启动。总体而言，这个项目寻求利用 有机会研究具有几个独特特征的结肠炎小鼠模型 这也与人类有关联，以便阐明细胞骨架的作用 白细胞在粘膜动态平衡中的调节。

DESCRIPTION (provided by applicant): The overall objective of this project is to gain further understanding of the mucosal immune system and the defects that contribute to the pathogenesis of human inflammatory bowel disease (IBD). The generation of a number of murine models of IBD has facilitated investigation into the basic mechanisms underlying IBD pathogenesis. Despite the fact that most murine models of IBD result from a defect in a single protein known to affect leukocyte function, the specific auto-reactive or regulatory cell population responsible for disease pathogenesis remains unknown. The Wiskott-Aldrich syndrome (WAS) is one of several immunodeficiencies that have been associated with autoimmunity, including IBD. We have recently generated a mouse model of IBD that results from the targeted disruption of the Wiskott-Aldrich syndrome protein (WASP). WASP is expressed solely in hematopoietic cells and is a signaling molecule that regulates cell surface receptor signals to the cytoskeleton. Abnormalities in this protein lead to the rare X-linked primary immunodeficiency that carries its name. The majority of WASP KO (WKO) mice also develop colitis. Our preliminary studies suggest that the colitis in WKO mice is unique, and perhaps more similar to human IBD than other murine models of IBD, because WASP-deficiency does not result in the loss of a specific T-cell class (e.g., alpha-beta T cells) or the absence of one specific cytokine (e.g., IL-2, IL-10 The development of each hematopoietic lineage is intact despite the fact that WASP regulates the actin cytoskeleton in all hematopoietic cells. In contrast with most murine models of IBD that have a Th1 bias, we demonstrate that lymphocytes isolated from the colonic lamina propria of WKO mice secrete a Th2 cytokine pattern. In addition, our genetic and adoptive transfer studies have established the requirement for lymphocytes in disease pathogenesis and the specific ability of CD4+ T-cells to transfer disease. Furthermore, WKO mice have a reduction in regulatory T-cells that are known to regulate autoimmunity in mice. Preliminary data also suggests that microbes play an essential role in disease pathogenesis. Interestingly, non-lethal irradiation leads to a dramatic increase in the severity of colitis with 100 percent disease penetrance. Our first aim is to define the role of WASP in regulatory and effector T-cell function and the contribution of additional leukocyte populations in IBD initiation and maintenance. Our second goal is to define the requirement of Th2 cytokines and the role of inflammatory and suppressor cytokines in colitis development. Our final goal of this proposal is to evaluate the role of bacteria and barrier function in colitis initiation in WKO mice. Overall, this project seeks to take advantage of the opportunity to study a murine model of colitis with several unique features that also has a human correlate in order to elucidate the role of cytoskeletal regulation of leukocytes in mucosal homeostasis.