TH2 CELLS DIRECT THE GENESIS OF COLONIC PATCHES AND IBD

TH2 细胞指导结肠斑块和 IBD 的发生

• 批准号: 6190082
• 负责人: Jerry R McGhee
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6190082
• 关键词: CD4 molecule; Peyer's patches; bacterial antigens; colitis; colon; cytokine; gel electrophoresis; helper T lymphocyte; inflammation; inflammatory bowel diseases; laboratory mouse; messenger RNA; microorganism immunology; mucosal immunity; passive immunization

Inflammatory bowel disease (IBD) are chronic, relapsing, tissue destructive disease. Recent advances in experimental models for IBD in mice have contributed to a better understand of the mechanisms of intestinal inflammation involving dysfunction of T cells and dysregulation of cytokine production. Notably, a central role for interferon-gamma (IFN-gamma) produced by T helper type 1 (Th1)-T cells and for inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been emphasized in these murine models. However, the immunological events which occur in human IBD are not always accommodated by these models. In ulcerative colitis, it is generally recognized that a role for TH1-type responses are not as evident as in Crohn's disease. In our recent investigation, we have obtained evidence that Th2-type responses are also much involved in a murine hapten-induced IBD model which is accompanied by expansion of colonic patches, which are the gut associated lymphoreticular tissues in the colon. Since inflammatory lesions were induced in a condition deficient in Th1 type cells producing IFN-gamma, and were distinct from the lesions seen in mice deficient in Th2 cytokines, we hypothesize that cytokine-phenotypes may explain the different pathological findings in ulcerative colitis and Crohn's disease. The major goal of this grant is to show that Th2-type responses can induce distinct types of lesions from those caused by Th1-type responses. Further, we will define colonic patches as inductive sites of chronic intestinal inflammation that occur through Th2 immune responses. To address this goal, the first aim will be to study the specific roles of Th2-type cells in murine intestinal inflammation through an adoptive transfer system of CD4+ CD45RB/Hi T cells. This study will be done with interactions with project 1 (Dr. Elson) in which adoptive transfer of Th1- or Th2-skewed T cells derived from C3H/HeJBir mice will also be investigated. In the second aim, we will define specific functions for colonic patches by comparing them with Peyer's patches for immune responses to defined antigens and delivery vectors/adjuvants which induced mucosal immunity via Th1- or Th2-type T cells. This study will interact with Project 2 (Dr. Weaver) for studies of antigen (OVA)-specific responses. The third aim will determine if colonic patches are necessary to induce intestinal inflammation by using mice deficient in organized colonic patches. Finally our last aim will define novel molecules which are specifically expressed in colonic patches using 2 dimensional gel analysis and differential display of mRNA between Peyer's and colonic patches. These latter techniques will also be applied to Project 4 (Dr. Leiter) to compare congenic stocks of mice which are done to develop inflammation. These proposed studies will provide new information for understanding the pathogenesis of non-Th1 type intestinal inflammation and the role of organized colonic patch lymphoid tissues in IBD.

炎症性肠病（IBD）是一种慢性、复发性、组织破坏性疾病。小鼠 IBD 实验模型的最新进展有助于更好地了解涉及 T 细胞功能障碍和细胞因子产生失调的肠道炎症机制。值得注意的是，在这些小鼠模型中，1 型辅助性 T (Th1)-T 细胞产生的干扰素-γ (IFN-γ) 和肿瘤坏死因子-α (TNF-α) 等炎症细胞因子的核心作用得到了强调。然而，这些模型并不总是适应人类 IBD 中发生的免疫事件。在溃疡性结肠炎中，人们普遍认为 TH1 型反应的作用并不像在克罗恩病中那么明显。在我们最近的研究中，我们获得的证据表明，Th2 型反应也与小鼠半抗原诱导的 IBD 模型密切相关，该模型伴随着结肠斑块的扩张，结肠斑块是结肠中与肠道相关的淋巴网状组织。由于炎症病变是在缺乏产生 IFN-γ 的 Th1 型细胞的情况下诱发的，并且与缺乏 Th2 细胞因子的小鼠中观察到的病变不同，我们假设细胞因子表型可以解释溃疡性结肠炎和克罗恩病的不同病理结果。该资助的主要目标是证明 Th2 型反应可以诱发与 Th1 型反应不同类型的病变。此外，我们将结肠斑定义为通过 Th2 免疫反应发生的慢性肠道炎症的诱导部位。为了实现这一目标，第一个目标是通过 CD4+ CD45RB/Hi T 细胞的过继转移系统研究 Th2 型细胞在小鼠肠道炎症中的具体作用。这项研究将通过与项目 1（Elson 博士）的相互作用来完成，其中还将研究源自 C3H/HeJBir 小鼠的 Th1 或 Th2 倾斜 T 细胞的过继转移。在第二个目标中，我们将通过将结肠补片与派尔氏补片进行比较来定义结肠补片的特定功能，以对特定抗原和通过 Th1 或 Th2 型 T 细胞诱导粘膜免疫的递送载体/佐剂产生免疫反应。这项研究将与项目 2（Weaver 博士）互动，研究抗原 (OVA) 特异性反应。第三个目标是通过使用缺乏有组织的结肠斑块的小鼠来确定结肠斑块是否是诱导肠道炎症所必需的。最后，我们的最后一个目标是使用二维凝胶分析和派耶氏斑块与结肠斑块之间 mRNA 的差异显示来定义在结肠斑块中特异性表达的新分子。后面这些技术也将应用于项目 4（Leiter 博士），以比较发生炎症的同源小鼠种群。这些拟议的研究将为了解非 Th1 型肠道炎症的发病机制以及有组织的结肠补片淋巴组织在 IBD 中的作用提供新的信息。