MUCOSAL IMMUNITY IN INTEGRIN ALPHA E DEFICIENT MICE

α-β整合素在粘膜上的选择性表达 淋巴细胞。虽然已知α-β与E-结合， 体外黏附实验检测上皮细胞上钙粘附素的表达 Alphaepsilon Beta的活体功能尚不清楚。在预赛中 研究表明，已经产生了缺乏α-受体表达的小鼠 通过基因打靶。这些Alphaepsilon动物的数量减少了 肠上皮内淋巴细胞和固有层 淋巴细胞。此外，在炎症性肠炎的体内模型中 疾病，从Bethaepsilon小鼠分离的CD_4/CD_4~+5RBhi细胞 产生比分离的细胞更轻的肠道炎症 Alphaepsilon+/+小鼠。因此，AlphaepsilonBeta似乎扮演着一个 在肠道炎症的发展中起着重要作用。 然而，α-epsilon缺乏导致 这些变化尚不清楚，因为整合素在外周血中表达 已知淋巴细胞在T淋巴细胞中很重要 外渗/本地化，发展，并作为共同的 刺激/黏附分子调节血管内皮细胞功能反应 T细胞对抗原的攻击。事实上，整合素往往发挥更多的调节作用。 在T淋巴细胞上表达时，不仅具有一种功能。在这 应用，提出了定义α功能(S)的研究 Epsilon Beta。在目标1中，Alphaepsilon Beta小鼠的iIEL发育 将通过T淋巴细胞亚群的FACS分析进行评估 以及iIEL细胞受体谱系的分析。在目标2中， αepsilon Beta和αepsilon+/+iIEL的粘附性 重组E-钙粘蛋白、固有层内皮细胞和固有层 将对固有层间质进行评估，并进行体内定位 Alphaepsilon Beta和Alphaepsilon+/+iIEL将在 采用迁移实验。在目标3中，α埃西隆的影响 淋巴细胞增殖、细胞因子等功能的表达 β细胞的产生、细胞毒作用及T细胞调节 将确定免疫球蛋白类开关，并将其比例 αepsilon+/+和αepsilon-/-中iIEL在活体中的增殖 老鼠将被比较。最后，在目标4和目标5中， 黏膜免疫应答中α-β-受体的表达 感染将通过体外和体内功能研究进行评估 以旋毛虫感染为模型。这些研究将提供 关于VIO中功能的重要信息(S) α-β整合素，并将用于评估 阻断α-β蛋白可作为IBD的一种治疗方法。

The alphaepsilonBeta integrin is expressed selectively on mucosal lymphocytes. While it is known that alphaepsilonBeta binds to E- cadherin expressed on epithelial cells in vitro adhesion assays, the in vivo functions of alphaepsilonBeta remain unknown. In preliminary studies, mice which lack alphaepsilon expression have been generated by gene targeting. These alphaepsilon animals have reduced numbers of intestinal intraephithelial lymphocytes and lamina propria lymphocytes. In addition, in an in vivo model of inflammatory bowel disease, CD 4/CD4+5RBhi cells isolated from bethaepsilon mice produced less severe intestinal inflammation than cells isolated from alphaepsilon+/+ mice. Thus, alphaepsilonBeta appears to play an important role in the development of intestinal inflammation. However, the mechanisms whereby alphaepsilon deficiency results in these changes are not clear, as integrins expressed on peripheral blood lymphocytes are known to be important in T lymphocyte extravasation/localization, development, and to act as co- stimulatory/adhesion molecules modulating the functional response of T cells to antigenic challenge. Indeed, integrins often mediate more than one function when expressed on T lymphocytes. In this application, studies are proposed to define the function(s) of alpha epsilon Beta. In aim 1, iIEL development in alphaepsilon Beta mice will be evaluated by FACS analysis of T lymphocyte subpopulations and analysis of the iIEL cell receptor repertoire. In aim 2, the adhesion of alphaepsilon Beta and alphaepsilon+/+ iIEL to recombinant E-caderin, lamina propria endothelial cells, and lamina propria interstitium will be evaluated, and the in vivo localization of alphaepsilonBeta and alphaepsilon+/+ iIEL will be compared in adoptive transfer experiments. In aim 3, the impact of alphaepsilon expression on lymphocyte functions including proliferation, cytokine production, cytotoxicity and T cell regulation of Beta cell immunoglobulin class switch will be determined, and the proportion of iIEL proliferating in vivio in alphaepsilon+/+ and alphaepsilon-/- mice will be compared. Finally, in aims 4 and 5 the impact of alphaepsilonbeta expression in the mucosal immune response to infection will be evaluated with in vitro and in vivo functional studies using T. spiralis infection as a model. These studies will provide important information about the in vio function(s) of the alphaepsilonbeta integrin and will used in evaluating the potential of blocking alphaepsilonbeta function as a treatment for IBD.