Regulation of Chronic Gut Inflammation

慢性肠道炎症的调节

• 批准号: 7026398
• 负责人: MATTHEW B GRISHAM
• 金额: $ 33.27万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026398
• 关键词: B lymphocyte; SCID mouse; affinity chromatography; athymic mouse; chronic disease /disorder; colitis; epithelium; flow cytometry; gene targeting; genetically modified animals; helper T lymphocyte; immunocytochemistry; immunoregulation; inflammatory bowel diseases; interleukin 10; polymerase chain reaction; transforming growth factors

DESCRIPTION (provided by applicant): Recent studies have described the ability of specific subsets of peripheral CD4+ T-cells to suppress chronic gut inflammation in immune-based models of inflammatory bowel disease (IBD). We have found that transfer of CD4+CD45RB[high] T-cells into athymic nu/nu (nude) mice fails to induce colitis whereas reconstitution with this same T-cell population into severe combined immunodeficient (SCID) or recombinase activating gene deficient (RAG -/-) mice induces severe colitis. These data suggest that in the absence of peripheral CD4+-T cells other lymphocyte populations may suppress the development of chronic colitis in this model. We provide preliminary data to suggest that intraepithelial lymphocytes (IELs) represent an equally important population of regulatory cells that act to prevent or limit the potentially injurious immune responses to enteric antigens. The overall objective of the present study is to better understand the mechanisms by which IELs prevent or limit chronic gut inflammation in vivo. Hypothesis: We propose that IELs represent an important regulatory cell population that are capable of inhibiting the initiation and progression of experimental colitis independent of peripheral CD4+ regulatory T-cells. This regulation may occur either through direct suppression of effector cell function or by promoting the polarization of naive CD4+ cells toward a non-pathogenic and/or regulatory phenotype. In addition, we propose that this suppressive activity of IELs is mediated by interleukin-10 (IL-10) and/or transforming growth factor-beta1 (TGF-beta). In order to test this hypothesis, we intend to: a) Determine whether IELs alone are capable of suppressing chronic colitis induced by the transfer of CD4+CD45RB[high] T-cells into immuno-deficient recipients. We will use two different approaches (i.e. radiation chimeras and breeding schemes) to generate immuno-deficient mice containing IELs but no T- or B-cells as well as mice containing B-cells but no IELs or T-cells; b) Define whether IELs regulate chronic gut inflammation by direct suppression of effector cell function or by promoting the polarization of naive CD4+CD45RB[high] T-cells toward a non-pathogenic and/or regulatory phenotype; and c) Identify whether IL-10 and/or TGF-beta mediate(s) the IEL-dependent suppression of chronic colitis in the CD45RB[high] T-cell/nude transfer model. Understanding the mechanisms by which IELs prevent or limit chronic gut inflammation may provide new insight into the pathophysiology of IBD.

描述（由申请人提供）：最近的研究描述了外周 CD4+ T 细胞的特定亚群在基于免疫的炎症性肠病 (IBD) 模型中抑制慢性肠道炎症的能力。我们发现，将 CD4+CD45RB[高] T 细胞转移到无胸腺 nu/nu（裸）小鼠中不能诱导结肠炎，而用相同的 T 细胞群重建为严重联合免疫缺陷（SCID）或重组酶激活基因缺陷（ RAG -/-) 小鼠诱发严重结肠炎。这些数据表明，在缺乏外周 CD4+-T 细胞的情况下，其他淋巴细胞群可能会抑制该模型中慢性结肠炎的发展。我们提供的初步数据表明，上皮内淋巴细胞（IEL）代表了同样重要的调节细胞群，其作用是预防或限制对肠道抗原的潜在有害免疫反应。本研究的总体目标是更好地了解 IEL 在体内预防或限制慢性肠道炎症的机制。假设：我们认为 IEL 代表了一种重要的调节细胞群，能够独立于外周 CD4+ 调节性 T 细胞抑制实验性结肠炎的发生和进展。这种调节可以通过直接抑制效应细胞功能或通过促进初始CD4+细胞向非致病性和/或调节表型的极化来发生。此外，我们认为 IEL 的这种抑制活性是由白介素 10 (IL-10) 和/或转化生长因子 β1 (TGF-β) 介导的。为了检验这一假设，我们打算： a) 确定单独的 IEL 是否能够抑制由 CD4+CD45RB[高] T 细胞转移至免疫缺陷受体引起的慢性结肠炎。我们将使用两种不同的方法（即辐射嵌合体和育种方案）来产生含有 IEL 但不含 T 或 B 细胞的免疫缺陷小鼠，以及含有 B 细胞但不含 IEL 或 T 细胞的小鼠； b) 确定 IEL 是否通过直接抑制效应细胞功能或通过促进初始 CD4+CD45RB[高] T 细胞向非致病性和/或调节表型极化来调节慢性肠道炎症； c) 确定 CD45RB[高] T 细胞/裸转移模型中 IL-10 和/或 TGF-β 是否介导 IEL 依赖性慢性结肠炎抑制。了解 IEL 预防或限制慢性肠道炎症的机制可能为 IBD 的病理生理学提供新的见解。