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， 导致人类炎症性肠病（IBD）的发病机制。的 许多IBD小鼠模型的产生促进了研究 IBD发病的基本机制。尽管事实上 大多数IBD的鼠模型是由已知的单一蛋白质缺陷引起的， 影响白细胞功能，特定的自身反应或调节细胞 负责疾病发病机制的人群仍然未知。的 Wiskott-Aldrich综合征（WAS）是几种免疫缺陷症之一， 与自身免疫有关，包括IBD。我们最近在一个 IBD的小鼠模型，其由靶向破坏 Wiskott-Aldrich综合征蛋白（WASP）。WASP仅在 造血细胞，是调节细胞表面的信号分子 受体信号传递到细胞骨架。这种蛋白质的缺失导致 一种罕见的X连锁原发性免疫缺陷，以其命名。大多数 WASP KO（WKO）小鼠也发生结肠炎。我们的初步研究表明， WKO小鼠中的结肠炎是独特的，并且可能比人类IBD更类似于人类IBD。 其他IBD小鼠模型，因为WASP缺乏不会导致 特定T细胞类别（例如，α-β T细胞）或缺乏一种 特异性细胞因子（例如，IL-2、IL-10各造血细胞的发育 尽管WASP调节肌动蛋白细胞骨架， 在所有造血细胞中。与大多数IBD小鼠模型相比， 有一个Th1的偏见，我们证明，淋巴细胞分离的结肠， WKO小鼠固有层分泌Th2细胞因子模式。另外我们 遗传和过继转移研究已经确定了以下要求： 淋巴细胞在疾病发病机制和CD4 + T细胞的特异性能力， 传染病此外，WKO小鼠的调节性T细胞减少， 调节小鼠自身免疫的基因初步数据还表明， 微生物在疾病发病机制中起着重要作用。有趣的是， 非致命性辐射导致结肠炎严重程度急剧增加 100%的患病率。我们的第一个目标是确定 WASP在调节和效应T细胞功能中的作用以及 IBD启动和维持中的额外白细胞群。我们的第二 目的是确定Th2细胞因子的需求和炎症因子的作用。 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 建议是评估细菌和屏障功能在结肠炎中的作用 在WKO小鼠中的起始。总的来说，该项目旨在利用 有机会研究具有几个独特特征的结肠炎小鼠模型 这也与人类相关，以阐明细胞骨架的作用， 在粘膜内环境稳定中调节白细胞。

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.