Inducing Immune Tolerance with Receptor Modified T Cells

描述（由申请人提供）： 尽管人们越来越了解 免疫性疾病的病理生理机制，抗原- 缺乏具体的治疗方法。抗原特异性疗法的发展是 这一点至关重要，因为非特异性治疗通常无法诱导持久的 缓解并受到显著毒性的限制。该提案描述了 一种新的抗原特异性免疫疗法的发展， 同种免疫疾病创建了遗传修饰的T细胞（GM-TC）， 能够特异性识别并破坏或转移病理性T细胞。 GM-TC通过替代T细胞受体来实现这一点，在单链中， 连接T细胞受体（TCR）信号传导结构域、MHC分子和抗原 缩氨酸病理性T细胞的TCR与免疫球蛋白互补并识别免疫球蛋白。 嵌合受体的MHC-抗原结构域。这种识别激活了 GM-TC通过嵌合受体的信号结构域。 GM-TC可以 增殖、分泌细胞因子并杀死病理性T细胞。初始 研究，收养性转让 GM-TC进入易感小鼠抑制 自身免疫性疾病提出了几个目标，以进一步探讨如何转基因技术合作伙伴 影响小鼠模型系统中的T细胞库以及GM-TC如何最好地 应用于治疗自身免疫和同种免疫病症。 信号转导 通过嵌合受体将被研究。 整合的效果 从共刺激和共受体分子的信号传导结构域进入嵌合 将分析受体以确定这些结构域是否可以增强 具体目标1（Specific Aim 1） 体外功能测定将用于 确定表达不同嵌合体的GM-TC的治疗潜力 受体。将进行T细胞功能和数量的定量测定 为了确定GM-TC对免疫库的体内影响（特异性免疫抑制）， 目标2）。 GM-TCs治疗实验性CD 4 + T细胞的有效性 介导的自身免疫性疾病（实验性自身免疫性脑脊髓炎）和 CD 8 + T细胞介导的同种异体免疫状况（皮肤移植排斥）将在 具体目标（3）。假设免疫调节性GM-TC将 通过破坏病理效应物下调自身免疫或同种免疫 细胞溶解性GM-TC将杀死同种免疫或自身免疫 效应T细胞将对GM-TC的细胞动力学和归巢特性进行研究。 分析以阐明影响治疗的体内细胞特性， 目标4（Specific Aim 4） 这些信息将提供一个开始 这是GM-TC在人类免疫条件下的应用点。

DESCRIPTION (provided by applicant): Despite an increasing understanding of the pathophysiologic mechanisms underlying immunologic diseases, antigen- specific therapies are lacking. Development of antigen-specific therapies is critical because nonspecific therapies are often unable to induce durable remissions and are limited by significant toxicities. This proposal describes the development of a novel antigen-specific immunotherapy for autoimmune and alloimmune diseases. Genetically modified T cells (GM-TCs) were created that are able to specifically recognize and destroy or divert pathologic T cells. The GM-TCs do this with surrogate T cell receptors that, in a single chain, link T cell receptor (TCR) signaling domains, MHC molecules, and antigenic peptides. The TCR of pathologic T cells is complementary to and recognizes the MHC-antigen domain of the chimeric receptor. This recognition activates the GM-TC through the chimeric receptor's signaling domain. The GM-TCs can proliferate, secrete cytokines, and kill the pathologic T cells. In initial studies, adoptive transfer of GM-TCs into susceptible mice suppressed autoimmune disease. Several aims are proposed to further explore how GM-TCs affect the T-cell repertoire in mouse model systems and how GM-TCs may best be applied to treat autoimmune and alloimmune conditions. Signal transduction through the chimeric receptors will be studied. The effect of integrating signaling domains from costimulatory and co-receptor molecules into chimeric receptors will be analyzed to determine whether these domains can enhance signaling (Specific Aim 1). In vitro functional assays will be used to determine the therapeutic potential of GM-TCs expressing different chimeric receptors. Quantitative assays of T cell function and number will be performed to determine the in vivo impact of GM-TCs on the immune repertoire (Specific Aim 2). The effectiveness GM-TCs in treating an experimental CD4+ T cell mediated autoimmune disease (experimental autoimmune encephalomyelitis) and a CD8+ T cell-mediated alloimmune condition (skin graft rejection) will be studied (Specific Aim 3). It is hypothesized that immunoregulatory GM-TCs will downmodulate autoimmunity or alloimmunity by disrupting pathological effector mechanisms and that cytolytic GM-TCs will kill alloimmune or autoimmune effecter T cells. The cell dynamics and homing properties of GM-TCs will be analyzed to clarify the in vivo cellular properties that influence therapeutic efficacy (Specific Aim 4). Together this information will provide a starting point for the application of GM-TCs to human immunologic conditions.