MUCOSAL IMMUNITY IN INTEGRIN ALPHA E DEFICIENT MICE

整合素 α E 缺陷小鼠的粘膜免疫

• 批准号: 2906082
• 负责人: CHRISTINA M PARKER
• 金额: $ 20.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906082
• 关键词: cadherins; cell adhesion; cytokine; disease /disorder model; flow cytometry; gastrointestinal epithelium; gene expression; gene rearrangement; gene targeting; immunoglobulin genes; inflammatory bowel diseases; integrins; laboratory mouse; lymphocyte proliferation; mucosal immunity; passive immunization

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.

α ε β整联蛋白选择性地在粘膜上表达， 淋巴细胞 虽然已知α ε β与E- 在体外粘附试验中，上皮细胞表达钙粘蛋白， α ε β的体内功能仍然未知。 初步 在研究中，已经产生了缺乏α-淀粉酶表达的小鼠， 通过基因靶向 这些阿尔法动物的数量 肠上皮内淋巴细胞和固有层 淋巴细胞 此外，在炎症性肠的体内模型中， 疾病，从贝塔斯曼小鼠分离的CD 4/CD 4 + 5 RBhi细胞 产生的肠道炎症比从 α 1 +/+小鼠。 因此，α ε β似乎扮演了一个 在肠道炎症的发展中起重要作用。 然而，α-淀粉酶缺乏导致 这些变化尚不清楚，因为外周血中表达的整合素 已知淋巴细胞在T淋巴细胞中是重要的 外渗/本地化，发展，并作为共同作用， 刺激/粘附分子调节的功能反应 T细胞抗原攻击。 事实上，整合素往往介导更多的 在T淋巴细胞上表达时， 在这 应用，研究提出了定义函数（S）的α 你是贝塔 在目标1中，在α-β小鼠中iIEL的发育 将通过T淋巴细胞亚群的FACS分析进行评价 和iIEL细胞受体库的分析。 在目标2中， α-淀粉酶β和α-淀粉酶+/+ iIEL与 重组E-钙粘蛋白、固有层内皮细胞和层 将评价固有层，并在体内定位 α ε β和α ε +/+ iIEL将在 过继转移实验 在目标3中， 对淋巴细胞功能的表达，包括增殖、细胞因子 β细胞的产生、细胞毒性和T细胞调节 免疫球蛋白类别转换将被确定， iIEL在α-和α-细胞内增殖 将小鼠进行比较。 最后，在目标4和5中， 粘膜免疫应答中的α ε β表达 将通过体外和体内功能研究评价感染 利用T. 螺旋感染作为模型。 这些研究将提供 关于体内功能的重要信息 α ε β整联蛋白，并将用于评估 阻断α ε β功能作为IBD的治疗。