TREATMENT OF AUTOIMMUNITY WITH RECEPTOR-MODIFIED T CELLS

描述（由申请人提供）：目前的自身免疫疗法通常无法诱导持久缓解，并受到显著毒性的限制。抗原特异性免疫疗法可能毒性更小，效力更强。因此，为使用这些技术制定科学依据至关重要。我们已经开发了一种新的抗原特异性免疫疗法用于治疗自身免疫。通过在T细胞上转基因表达连接自身抗原-MHC和来自TCR的信号传导区域的嵌合受体，我们能够特异性地重定向治疗性T细胞以对抗自身反应性T细胞。嵌合受体与自身反应性T细胞的TCR的接合刺激治疗性细胞的内源性免疫调节功能。在初步研究中，我们已经表明，表达这些嵌合受体的T细胞（受体修饰的T细胞，RMTC）在治疗模型自身免疫性疾病，实验性过敏性脑脊髓炎（EAE）中是非常有效的。我们的研究结果导致了几个假设。假设1：RMTC可用于治疗人类自身免疫性疾病。我们的初步结果表明，用针对对一种自身抗原表位特异性的T细胞的RMTC治疗自身免疫可以全面下调自身免疫应答。我们将创建针对多发性硬化患者中发现的自身反应性T细胞的人源化RMTC，并测试是否可以在临床前模型中实现类似的效力。假设2：RMTC形成一个治疗性细胞家族，通过不同的机制耐受自身反应性T细胞。我们的初步结果表明，CD 8+，CD 4 + CD 25+，和Th 2 RMTC，而不是其他RMTC类型是有效的缓解EAE。因此，我们将研究这些RMTC子集的作用机制。我们将进一步分析通过靶向自身反应性T细胞，RMTC是否可以抑制胶原诱导的关节炎中自身抗体的产生和病理。假设3：RMTC改变自身反应性T细胞的迁移和细胞动力学。我们将定量分析RMTC及其自身反应性靶细胞的迁移和寿命。平行研究将评估RMTC与其体内靶标的共定位。假设4：RMTC的功能能力取决于嵌合受体对同源TCR的亲合力和信号传导结构域效力。我们将确定靶细胞的抗原亲合力、RMTC的嵌合受体表达水平和嵌合受体信号传导结构域的效力如何影响RMTC应答。这些研究将增强我们对抗原特异性免疫疗法如何下调主动自身免疫反应的理解，并为RMTC和其他细胞治疗方法的应用提供科学依据。

DESCRIPTION (provided by applicant): Current therapies for autoimmunity are frequently unable to induce durable remissions and are limited by significant toxicities. Antigen-specific immunotherapies may be less toxic and more potent. Formulating a scientific basis for their use is therefore critical. We have developed a novel antigen-specific immunotherapy for the treatment of autoimmunity. By transgenically expressing on T-cells chimeric receptors that link autoantigen-MHC and signaling regions from the TCR we are able to specifically redirect therapeutic T-cells against autoreactive T-cells. Engagement of the chimeric receptor by the autoreactive T-cell's TCR stimulates endogenous immunoregulatory functions of the therapeutic cell. In preliminary studies we have shown that T cells expressing these chimeric receptors (receptor-modified T-cells, RMTC) are highly effective in treating a model autoimmune disease, experimental allergic encephalomyelitis (EAE). Our results have led to several hypotheses. Hypothesis 1: RMTC may be applied to treat human autoimmune disease. Our preliminary results showed that treatment of autoimmunity with RMTC directed against T cells specific for one autoantigenic epitope can globally down modulate the autoimmune response. We will create humanized RMTC specific for autoreactive T cells found in patients with multiple sclerosis and test whether similar potency can be achieved in pre-clinical models. Hypothesis 2: RMTC form a family of therapeutic cells that tolerize autoreactive T-cells through different mechanisms. Our preliminary results showed that CD8 +, CD4+CD25 +,and Th2 RMTC, but not other RMTC types are effective in alleviating EAE. We will therefore study the mechanism of action of these RMTC subsets. We will further analyze whether, by targeting autoreactive T cells, RMTC can suppress autoantibody production and pathology in collagen-induced arthritis. Hypothesis 3: RMTC modify the migration and cellular dynamics of autoreactive T cells. We will quantitatively analyze the migration and longevity of RMTC and their autoreactive target cells. Parallel studies will assess the colocalization of RMTC with their targets in vivo. Hypothesis 4: The functional capabilities of RMTC depend upon chimeric receptor avidity for cognate TCR and signaling domain potency. We will determine how a target cell's antigen avidity, the RMTC's chimeric receptor expression level, and the chimeric receptor signaling domain's potency influence RMTC response. These studies will enhance our understanding of how active autoimmune responses can be downmodulated by antigen-specific immunotherapies and provide a scientific basis for the application of RMTC and other cellular therapeutic approaches.