EFFECT OF ADENOVIRUS E3 IMMUNOREGULATORY PROTEIN ON ALLOGENIC TRANSPLANTATION

腺病毒E3免疫调节蛋白对异体移植的影响

• 批准号: 6301163
• 负责人: MARSHALL S. HORWITZ
• 金额: $ 22.79万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-21 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301163
• 关键词: Adenoviridae; MHC class I antigen; NOD mouse; diabetes mellitus; diabetes mellitus therapy; disease /disorder prevention /control; genetically modified animals; homologous transplantation; immediate early protein; immunomodulators; lymphocyte; microorganism immunology; nonhuman therapy evaluation; pancreatic islet transplantation; transplantation immunology; tumor necrosis factor alpha

Human adenoviruses (Ads) encode a number of proteins that modulate the host responses against virus-infected cells. These proteins, whose genes are clustered in the early region 3 (E3) transcription unit, can (1) control transport of the class I major histocompatibility complex (MHC) heavy chain from the endoplasmic reticulum (ER) to the cell surface and (2) inhibit cytolysis induced by tumor necrosis factor alpha (TNFalpha). We postulated that the anti-class I MHC and anti-TNF effects of the Ad E3 genes may be used to facilitate allogenic pancreatic beta-cell transplantation and prevent autoimmune diabetes. Experiments have been performed in transgenic mice carrying the entire Ad2 E3 transcription region behind the rat insulin promoter (RIP) to test these hypothesis. Both tolerization to long-term allogeneic transplantation and prevention of lymphocytic choriomeningitis virus (LCMV)-induced autoimmune diabetes have been achieved in the presence of the Ad E3 transgenes expressed in islets. Encouraged by these initial results, we wish to extend these observations into new area of investigation by studying the contributions of individual Ad E3 gene products in the transplantation and LCMV models as well as introduce the Ad E3 immunoregulatory gene functions into the islets of nonobese diabetic (NOD) mice. The Ad E3 genes will also be inserted into a conditionally immortalized and growth controlled murine beta-cell line for the long term correction of diabetes by allogeneic transplantation.

人腺病毒（Ads）编码多种蛋白质， 宿主对病毒感染的细胞作出反应。这些蛋白质， 基因聚集在早期区域3（E3）转录单位中，可以（1） 控制I类主要组织相容性复合体（MHC）的转运 重链从内质网（ER）到细胞表面， (2)抑制肿瘤坏死因子α（TNF α）诱导细胞溶解。 我们推测，AdE3的抗I类MHC和抗TNF作用 基因可用于促进同种异体胰腺β细胞 预防自身免疫性糖尿病。实验已经 在携带完整Ad2 E3转录的转基因小鼠中进行 大鼠胰岛素启动子（RIP）后面的区域来验证这些假设。 对长期同种异体移植的耐受和预防 淋巴细胞性脉络丛脑膜炎病毒（LCMV）诱导的自身免疫性糖尿病 已经在表达的Ad E3转基因的存在下实现， 小岛在这些初步成果的鼓舞下，我们希望将这些成果 通过研究贡献，观察新的调查领域 单个Ad E3基因产物在移植和LCMV模型中的表达 并将Ad E3免疫调节基因功能导入 非肥胖糖尿病（NOD）小鼠的胰岛。Ad E3基因也将被 插入到条件永生化和生长控制的小鼠中， 用于通过同种异体移植长期纠正糖尿病的β细胞系 移植