TREATMENT OF AUTOIMMUNITY WITH RECEPTOR-MODIFIED T CELLS

描述(申请人提供)：目前的自身免疫疗法往往不能诱导持久的缓解，并受到重大毒性的限制。抗原特异性免疫疗法可能毒性更小，效果更好。因此，为它们的使用制定科学基础是至关重要的。我们开发了一种新的抗原特异性免疫疗法来治疗自身免疫。通过在连接自身抗原-MHC和TCR信号区的T细胞嵌合受体上转基因表达，我们能够特异性地将治疗性T细胞重新定向到自身反应性T细胞。嵌合受体与自身反应性T细胞的TCR结合可刺激治疗细胞的内源性免疫调节功能。在初步研究中，我们已经证明，表达这些嵌合受体的T细胞(受体修饰的T细胞，RMTC)在治疗实验性变态反应性脑脊髓炎(EAE)模型自身免疫性疾病方面非常有效。我们的结果引出了几个假设。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，针对一个自身抗原表位的T细胞用RMTC治疗自身免疫可以全局下调自身免疫反应。我们将为多发性硬化症患者中发现的自身反应性T细胞创建人源化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，CD8+、CD4+CD25+和Th2 RMTC在缓解EAE方面是有效的，但不是其他类型的RMTC。因此，我们将研究这些RMTC亚集的作用机制。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的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及其自身反应靶细胞的迁移和寿命。平行研究将评估RMTC与其体内靶点的共定位。假设4：RMTC的功能取决于嵌合受体对同源TCR的亲和力和信号域的效力。我们将确定靶细胞的抗原亲和力、RMTC的嵌合受体表达水平和嵌合受体信号域的效力如何影响RMTC反应。这些研究将加深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.