Regulation of Chronic Gut Inflammation

描述(申请人提供)：最近的研究描述了在基于免疫的炎症性肠病(IBD)模型中，特定的外周CD4+T细胞亚群抑制慢性肠道炎症的能力。我们发现，将CD4+CD45Rb[High]T细胞转移到裸鼠体内不能诱发结肠炎，而将相同T细胞群重组到严重联合免疫缺陷(SCID)或重组酶激活基因缺陷(RAG-/-)小鼠中则会导致严重的结肠炎。这些数据表明，在这个模型中，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)代表着同样重要的调节细胞群，它们起到预防或限制对肠道抗原的潜在破坏性免疫反应的作用。本研究的总体目标是更好地了解IELs在体内预防或限制慢性肠炎的机制。假设：我们认为IEL是一个重要的调节细胞群，能够抑制实验性结肠炎的发生和发展，而不依赖于外周的CD4+调节T细胞。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的CD4+细胞向非致病性和/或调节性表型的极化来发生。此外，我们认为IELs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。为了验证这一假设，我们打算：a)确定IEL是否能够单独抑制由将CD4+CD45RB[高]T细胞转移到免疫缺陷受体体内而引起的慢性结肠炎。我们将使用两种不同的方法(即放射嵌合体和育种方案)来产生免疫缺陷小鼠，包括含有IEL但没有T或B细胞的小鼠；b)确定IEL是通过直接抑制效应细胞功能还是通过促进初始CD 4+CD45RB[高]T细胞向非致病和/或调节表型的极化来调节慢性肠炎；以及c)在CD45RB[高]T细胞/裸转移模型中，确定IL-10和/或转化生长因子-β是否介导IEL依赖的慢性结肠炎的抑制作用。了解IEL预防或限制慢性肠道炎症的机制可能会为IBD的病理生理学提供新的见解。

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.