Inducing Immune Tolerance with Receptor Modified T Cells

描述(申请人提供)：尽管人们对免疫疾病的病理生理机制有了越来越多的了解，但抗原- 目前还缺乏特定的治疗方法。抗原特异性疗法的发展是 至关重要，因为非特异性治疗往往不能产生持久的效果 缓解，并受到重大毒性的限制。这份提案描述了 一种新的抗原特异性免疫疗法治疗自身免疫性疾病的研究进展 同种异体免疫疾病。转基因T细胞(GM-TC)被创造出来 能够特异性地识别和破坏或转移病理性T细胞。 GM-TC通过代理T细胞受体做到这一点，在单链中， 链接T细胞受体(TCR)信号域、MHC分子和抗原性 多肽。病理性T细胞的TCR是对TCR的补充和识别 MHC-嵌合受体的抗原域。这一认可激活了 GM-TC通过嵌合受体的信号域。GM-TCS可以 增殖、分泌细胞因子，并杀死病理性T细胞。在首字母中 研究，GM-TCS过继转移到易感小鼠被抑制 自身免疫性疾病。提出了几个目标，以进一步探讨GM-TCS如何 影响小鼠模型系统中的T细胞谱系，以及GM-TCS可能的最佳效果 应用于治疗自身免疫和同种异体免疫疾病。信号转导 通过嵌合受体进行研究。整合的效果 从共刺激分子和共受体分子到嵌合体的信号域 将对受体进行分析，以确定这些结构域是否可以增强 发信号(具体目标1)。体外功能分析将被用来确定GM-TCS表达不同嵌合的治疗潜力 感受器。将进行T细胞功能和数量的定量分析 确定GM-TCS对免疫谱系的体内影响(特异性 目标2)。GM-TCS对实验性CD4+T细胞的作用 介导性自身免疫性疾病(实验性自身免疫性脑脊髓炎)和 CD8+T细胞介导的同种异体免疫状态(皮肤移植排斥反应)将 研究(具体目标3)。据推测，免疫调节GM-TCS将 通过破坏病理效应来下调自身免疫或同种异体免疫 细胞溶解GM-TCS杀伤同种或自身免疫的机制 效应性T细胞。GM-TCS的细胞动力学和归巢特性将是 分析以阐明影响治疗效果的体内细胞属性 功效(具体目标4)。这些信息将提供一个开始 GM-TCS在人体免疫条件下的应用要点。

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.