Role of Integrin alphaEbeta7 on Th2 Immune Responses

整合素 alphaEbeta7 对 Th2 免疫反应的作用

• 批准号: 6344613
• 负责人: CHRISTINA M PARKER
• 金额: $ 20.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344613
• 关键词: Trichinella; cell differentiation; cell migration; cellular immunity; eosinophil; helper T lymphocyte; hypersensitivity; inflammation; integrins; interferon gamma; interleukin 10; interleukin 3; interleukin 4; interleukin 5; laboratory mouse; mast cell; monoclonal antibody; protein biosynthesis; respiratory hypersensitivity; trichinosis

Th2 cytokines interleukin (IL)-4, 5, 9, 10 and granulocyte macrophage-colony stimulating factor, and the Th1/2 cytokine IL-3 have been importantly implicated as characterizing the immune responses in pathological allergic conditions. The differentiation, recruitment and activation of T cells, eosinophils and mast cells that produce or are regulated by these cytokines represent central components of these responses. Here, we define a previously unappreciated role for the mucosal integrin alphaEbeta7 in Th2 biased immunological responses. This integrin in predominantly expressed on mucosal T cells and can be induced on mast cells and certain dendritic cells, but is otherwise not expressed in the animal. We recently developed an alphaE deficient mouse that, together with blocking anti-alphaE specific monoclonal antibodies, have revealed an important role for this integrin in Th2 biased mucosal immune responses. Preliminary studies revealed that alphaE deficient (alphaE-/-) mice developed less pulmonary inflammation and airway hyperactivity after aerosolized ovalbumin exposure than wildtype (alphaE+/+) mice. Thus, in Aim 1, this finding will be confirmed in alphaE+/+ and alphaE-/- mice on an inbred genetic background and in alphaE+/+ mice after treatment with an ani-alphaEbeta7 monoclonal antibody, and will be extended to compare lymphocyte localization and phenotype. In Aim 2, T lymphocyte cytokine production by selected T cell subsets will be compared after aerosolized ovalbumin exposure in alphaE-/- and alphaE+/+ mice, and adoptive transfer experiments will be performed to define T cell subpopulations that can reconstitute the pulmonary response in alphaE-/- mice. These studies will reveal the role of alphaEbeta7 in this Th2 T cell/eosinophil based inflammation. The mast cell component of the allergic response is not readily studied in the pulmonary inflammation model. Thus, using a helminth infection model that induced T cell dependent reactive mast cell hyperplasia, we found the response to be augmented in alphaE deficient mice. In Aim 3, Trichinella spiralis induced mast cell hyperplasia will be compared in alphaE-/- and alphaE+/+ mice on an inbred genetic background, and in alphaE+/+ mice after treatment with anti-alphaEbeta7 antibodies. These studies are expected to confirm the important role of alphaEbeta7, and the cells that express it, in reactive mast cell hyperplasia. In addition, the impact of alphaE deficiency on T. spiralis induced mast cell progenitor recruitment, mucosal mast cell migration/differentiation, or resolution will be defined. In Aim 4, a mechanism will be sought for the enhanced reactive mast cell hyperplasia through the comparative study of T. spiralis induced changes in T cell localization and cytokine production, and adoptive transfer studies will be performed to determine whether it is alphaE deficiency on the T cells or the mast cells or both that results in augmented T. spiralis induced reactive mast cell hyperplasia.

Th2细胞因子白细胞介素(IL)- 4,5,9,10和粒细胞巨噬细胞集落刺激因子，以及Th1/2细胞因子IL-3在病理性过敏条件下的免疫反应中具有重要意义。产生或受这些细胞因子调节的T细胞、嗜酸性粒细胞和肥大细胞的分化、募集和活化是这些反应的核心组成部分。在这里，我们定义了粘膜整合素alphaEbeta7在Th2偏向性免疫反应中以前未被认识到的作用。这种整合素主要在粘膜T细胞上表达，并可在肥大细胞和某些树突状细胞上诱导表达，但在动物中不表达。我们最近开发了一种α e缺陷小鼠，与阻断抗α e特异性单克隆抗体一起，揭示了该整合素在Th2偏向性粘膜免疫反应中的重要作用。初步研究显示，与野生型（α e +/+）小鼠相比，α e缺乏（α e -/-）小鼠在雾化卵清蛋白暴露后出现较少的肺部炎症和气道亢进。因此，在Aim 1中，这一发现将在具有近交系遗传背景的alphaE+/+和alphaE-/-小鼠以及经过抗alphaebeta7单克隆抗体治疗的alphaE+/+小鼠中得到证实，并将扩展到比较淋巴细胞定位和表型。在Aim 2中，将比较雾化卵白蛋白暴露于α e -/-和α e +/+小鼠后，选定的T细胞亚群产生的T淋巴细胞细胞因子，并进行过继转移实验，以确定可以重建α e -/-小鼠肺反应的T细胞亚群。这些研究将揭示alphabeta7在Th2 T细胞/嗜酸性粒细胞炎症中的作用。肥大细胞成分的过敏反应是不容易研究在肺部炎症模型。因此，使用蠕虫感染模型诱导T细胞依赖性反应性肥大细胞增生，我们发现在α e缺陷小鼠中反应增强。在Aim 3中，旋毛虫诱导的肥大细胞增生将在近交遗传背景下的alphaE-/-和alphaE+/+小鼠中以及在抗alphaebeta7抗体治疗后的alphaE+/+小鼠中进行比较。这些研究有望证实alphaEbeta7及其表达细胞在反应性肥大细胞增生中的重要作用。此外，α - e缺乏对螺旋螺旋体诱导的肥大细胞祖细胞募集、粘膜肥大细胞迁移/分化或溶解的影响将被确定。在Aim 4中，我们将通过比较研究螺旋螺旋体诱导的T细胞定位和细胞因子产生的变化来寻找增强反应性肥大细胞增生的机制，并进行过继转移研究，以确定是T细胞或肥大细胞上的α e缺乏，还是两者都缺乏导致螺旋螺旋体诱导的增强反应性肥大细胞增生。