PILOT--INDUCTION OF T CELL TOLERANCE TO ANTIVIRAL VECTOR

描述（改编自应用程序）： 在基于腺病毒的基因治疗中一个未解决的问题是诱导一个 快速消除感染细胞和消除转基因的免疫反应 表情尽管从免疫球蛋白中删除某些抗原结构， 腺病毒提高了转基因表达的延长， 反应和随后的组织炎症仍然是主要问题， 腺病毒基因治疗的应用。因此，这是合理的， 期望设计免疫干预策略以诱导特异性免疫应答， 对腺病毒载体的耐受性。此应用程序的总体目标是 测试通过同基因抗原诱导特异性耐受创新策略 Fas配体的抗原提呈细胞（APCs）。核心假设是， 当APC将腺病毒抗原呈递给应答T细胞时， 这些APC表达的Fas配体水平可诱导细胞凋亡， 腺病毒特异性T细胞。因此，将宿主暴露于腺病毒载体， 感染的表达Fas配体的APC会导致特异性T细胞的耗竭， 细胞群，并因此诱导对腺病毒的免疫耐受 vector.对腺病毒载体的免疫应答降低， 来自T细胞的转染的宿主细胞攻击并延长转基因表达。 此外，如果转基因产品是免疫原性的，那么T细胞耐受性可以是免疫原性的。 以类似的方式诱导。为了验证这一假设，我们将首先确定 腺病毒载体的免疫耐受是否可以通过 表达Fas配体的腺病毒抗原呈递细胞;然后确定 用表达Fas的腺病毒抗原呈递细胞治疗 配体提高了腺病毒基因治疗在动物模型中的功效 囊性纤维化本申请将介绍一种新颖且强大的 基于腺病毒载体基因治疗设计的免疫干预策略 以抑制炎症反应并延长转基因表达。的 这项应用的完成可能会改善腺病毒基因治疗在 囊性纤维化的治疗

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.