PILOT--INDUCTION OF T CELL TOLERANCE TO ANTIVIRAL VECTOR

试点--诱导 T 细胞对抗病毒载体的耐受

• 批准号: 6564365
• 负责人: TONG ZHOU
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564365
• 关键词: Adenoviridae; CD95 molecule; T lymphocyte; antigen presenting cell; apoptosis; cystic fibrosis; gene therapy; genetically modified animals; immune tolerance /unresponsiveness; laboratory mouse; transfection /expression vector

Description (adapted from the application): An unsolved problem in adenovirus-based gene therapy is the elicitation of an immune response that rapidly eliminates infected cells and ablates transgene expression. Although deletion of certain antigenic structure from the adenovirus improves the prolongation of transgene expression, the immune response and the subsequent tissue inflammation remain major problems in the application of adenovirus based gene therapy. Thus, it is both reasonable and desirable to design an immunointervention strategy to induce specific immune tolerance to the adenoviral vector. The overall goal of this application is to test an innovative strategy to induce specific tolerance by syngeneic antigen presenting cells (APCs) that express Fas ligand. The central hypothesis is that when the APCs present adenoviral antigens to the responding T cells, high levels of Fas ligand expression by these APCs would induce apoptosis of adenovirus specific T cells. Thus, exposure of host to adenoviral vector infected APCs expressing Fas ligand would lead to depletion of a specific T cell population, and therefore induce immune tolerance to the adenoviral vector. The decreased immune response to the adenoviral vectors would protect the transfected host cells from T cell attack and prolong transgene expression. Moreover, if transgenic products are immunogenic, then T cell tolerance can be induced in a similar manner. To test this hypothesis, we will first determine whether immune tolerance to adenoviral vectors can be specifically induced by adenoviral antigen presenting cells that express Fas ligand; and then determine whether treatment with adenoviral antigen presenting cells that express Fas ligand improves the efficacy of adenoviral gene therapy in an animal model of cystic fibrosis. The present application will introduce a novel and powerful immunointervention strategy into adenoviral vector based gene therapy designed to inhibit the inflammatory response and prolong transgene expression. The accomplishment of this application might improve adenoviral gene therapy in the treatment of cystic fibrosis.

说明(改编自应用程序)： 腺病毒为基础的基因治疗中一个尚未解决的问题是诱导 快速清除感染细胞和消除转基因的免疫反应 表情。虽然某些抗原性结构从 腺病毒改善转基因表达的延长，免疫 反应和随之而来的组织炎症仍然是 腺病毒载体在基因治疗中的应用。因此，它既合理又合理。 希望设计一种免疫干预策略来诱导特异性免疫 对腺病毒载体的耐受性。此应用程序的总体目标是 测试一种通过同种抗原诱导特异性耐受的创新策略 表达Fas配体的提呈细胞(APC)。中心假设是 当APC将腺病毒抗原呈递给有反应的T细胞时，高 这些APC表达Fas配体的水平会诱导细胞凋亡 腺病毒特异性T细胞。因此，宿主对腺病毒载体的暴露 感染的表达Fas配体的APC会导致特定T细胞的耗尽 细胞群，从而诱导对腺病毒的免疫耐受 向量。对腺病毒载体免疫反应的降低将保护 转基因宿主细胞受到T细胞的攻击，延长了转基因的表达。 此外，如果转基因产品是免疫原性的，那么T细胞的耐受性可以 以类似的方式诱导。为了检验这一假设，我们首先要确定 能否特异性地诱导对腺病毒载体的免疫耐受 表达Fas配体的腺病毒抗原提呈细胞；然后确定 是否对腺病毒抗原提呈细胞表达Fas的治疗 配基对腺病毒基因治疗的作用 囊性纤维化。本申请将介绍一种新颖而强大的 腺病毒载体基因治疗的免疫干预策略设计 抑制炎症反应，延长转基因表达。这个 这一应用的完成可能会改进腺病毒的基因治疗 囊性纤维化的治疗。