The Pathogenesis Of Colitis In A Novel Th2 Model Of IBD

新型 IBD Th2 模型中结肠炎的发病机制

• 批准号: 6418028
• 负责人: Scott B Snapper
• 金额: $ 32.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-05 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6418028
• 关键词: Wiskott Aldrich syndrome; antiinfective agents; autoimmune disorder; cell population study; colitis; cytokine; disease /disorder etiology; disease /disorder model; gene targeting; genetically modified animals; helper T lymphocyte; inflammatory bowel diseases; laboratory mouse; mucosal immunity; pathologic process

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.

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