TREATMENT OF EAE USING GENETICALLY MODIFIED CTL

自身反应性T淋巴细胞(ATL)是重要的调节和 多发性硬化症和其他自身免疫的效应细胞 疾病。根除这些ATL可能会改善或治愈这种 疾病。能够选择性地针对ATL的治疗方法不是 在临床上可用。本提案描述了一种 使用转基因细胞溶解T细胞的新疗法 淋巴细胞(GM-CTL)选择性清除ATL。通用汽车- CTL将被转染一种嵌合受体，能够同时 识别ATL并激活GM-CTL。这个受体将 包括：A类主要组织相容性复合体(MHC) α链和β链，B.共价连接抗原肽，以及 C.T细胞受体Zeta链的激活域。这个 ALT T细胞受体将与NHC- 嵌合受体的多肽复合体。此交互将 激活GM-CTL，进而杀死ATL。通过使用 GM-CTL选择性消除ATL应该有可能 调节或根除正在发生的自身免疫性疾病。这将是 使用一种具有良好特性的小鼠模型进行测试 实验性硬化症和接种疫苗后的脑脊髓炎 过敏性脑脊髓炎(EAE)。嵌合式建筑设计将 通过体外GM-CTL活性测定进行优化。GM-CTL 然后在并发之前被采用转移到小鼠体内 在诱发EAE的情况下或之后。病理和临床 将对结果的衡量标准进行评估。这些实验将 从而提供评估转基因有用性的初步研究-- CTL在治疗自身免疫性神经系统疾病中的作用它将建立 类似使用GM-CTL治疗急性髓细胞白血病的先例 人类自身免疫性疾病。

Autoreactive T lymphocytes (ATL) are critical regulatory and effector cells for multiple sclerosis and other autoimmune diseases. Eradication of these ATL may ameliorate or cure such diseases. Therapies capable of selectively targeting ATL are not available clinically. This proposal describes the development of a novel therapy that uses genetically modified cytolytic T lymphocytes (GM-CTL) to selectively eliminate ATL. The GM- CTL will be transfected with a chimeric receptor capable of both recognizing ATL and activating the GM-CTL. This receptor will consist of: a class II major histocompatibility complex (MHC) alpha and beta chains, b. covalently linked antigenic peptide, and c. the activation domain of the T cell receptor zeta chain. The ALT T-cell receptor will specifically interact with the NHC- peptide complex of the chimeric receptor. This interaction will activate the GM-cTL, which in turn will kill the ATL. By using GM-CTL to selectively eliminate ATL it should be possible to modulate or abrogate ongoing autoimmune disease. This will be tested using a well characterized murine model for multiple sclerosis and post-vaccination encephalomyelitis, experimental allergic encephalomyelitis (EAE). Chimeric construct design will be optimized using in vitro assays of GM-CTL activity. GM-CTL will then be adoptively transferred into mice prior to, concurrent with, or following the induction of EAE. Pathologic and clinical measures of outcome will be assessed. These experiments will thus provide the initial studies assessing the usefulness of GM- CTL in treating autoimmune neurologic disease. It will establish a precedent for the analogous use of GM-CTL as a therapy for human autoimmune disease.