CAR-T cell treatment of CNS Autoimmunity

项目摘要 存在对选择性和抗原特异性免疫疗法而不存在全局免疫抑制的巨大需求 对于自身免疫性疾病，如多发性硬化症（MS）和一种密切相关的称为髓鞘的疾病， 少突胶质细胞糖蛋白（MOG）抗体病（MOGAD）。这促使了对嵌合体的探索 抗原受体（CAR）T细胞利用以特异性消除自身反应性细胞。我们创造了一个独特的 CAR T细胞的版本，其中肽MHCII（pMHCII）与信号传导结构域融合以识别 特异性T细胞受体（TCR）。在初步研究中，我们证明这些pMHCII-CAR T细胞 在体外特异性识别同源TCR，并在体内选择性杀死抗原特异性CD 4 T细胞。高效 高亲和力MOG特异性CD 4 T细胞的耗竭与MOG诱导的实验性免疫缺陷的预防有关。 自身免疫性脑脊髓炎（EAE），MS的动物模型。 更有效地消除低亲和力MOG反应性T细胞，这与缓解 持续EAE。这些数据表明，自身免疫的“活化能”模型类似于化学物质的“活化能”模型。 反应，其中需要更高亲和力的自身反应性T细胞来提供活化能以启动 免疫性T细胞是自身免疫性T细胞，但亲和力较低的T细胞能够维持自身免疫性“反应”。解决 假设CAR T细胞技术可用于消除自身抗原特异性T细胞并消除中枢免疫应答， 在没有全面免疫抑制的情况下，我们在小鼠和人类的神经系统（CNS）自身免疫中， 提出了三个具体目标。在目的1中，我们将提高体内低亲和力T细胞缺失的效率。在Aim中 2，我们将测试我们是否可以成功地靶向自身反应性CD 4 T细胞特异性的所有T细胞表位， 我们预测，这种方法将有助于治疗人类疾病， T细胞自身抗原由自身抗体鉴定。最后，在目标3中，我们将直接测试MOGAD患者是否 显示使用pMHCII-CAR用于抗原发现的MOG特异性T细胞的频率增加。总之，我们的 拟议的研究将探索自身免疫的“活化能”模型，并建立最佳的CAR T细胞， 消除低亲和力自身反应性TCR特异性的方法，用于治疗正在进行的自身免疫性疾病。 最后，我们将开始将这些鼠的观察结果转化为人pMHCII-CAR T细胞，并评估它们的表达。 在相关的人类自身免疫性CNS疾病中的潜在效用。

PROJECT SUMMARY An immense need for selective and antigen-specific immunotherapy without global immunosuppression exists for autoimmune diseases such as multiple sclerosis (MS) and a closely related condition known as myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). This has prompted exploration of chimeric antigen receptor (CAR) T cell utilization to specifically eliminate autoreactive cells. We have created a unique version of CAR T cells in which peptide MHCII (pMHCII) was fused with signaling domains in order to recognize specific T cell receptors (TCRs). In preliminary studies we demonstrate that these pMHCII-CAR T cells specifically recognize a cognate TCR in vitro and can selectively kill antigen-specific CD4 T cells in vivo. Efficient depletion of high affinity MOG-specific CD4 T cells was associated with prevention of MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Modifications in pMHCII-CAR construction led to greater efficiency in eliminating lower-affinity MOG-reactive T cells which was associated with resolution of ongoing EAE. These data suggest an “activation energy” model of autoimmunity analogous to that of a chemical reaction, in which higher affinity self-reactive T cells are needed to provide the activation energy to initiate autoimmunity, but lower affinity T cells are capable of sustaining the autoimmune “reaction.” To address the hypothesis that CAR T cell technology can be used to eliminate auto-antigen-specific T cells and abrogate central nervous system (CNS) autoimmunity in mice and humans without global immunosuppression, we have formulated three specific aims. In Aim 1 we will improve the efficiency of low affinity T cell deletion in vivo. In Aim 2, we will test whether we can successfully target autoreactive CD4 T cells specific to all T cell epitopes of a protein in mice, as we predict that such an approach would be useful for treatment of human disease where the T cell autoantigen is identified by an autoantibody. Finally, in Aim 3, we will directly test whether MOGAD patients show an increased frequency of MOG-specific T cells using pMHCII-CARs for antigen discovery. In sum, our proposed studies will explore the “activation energy” model of autoimmunity and establish an optimal CAR T cell approach to eliminate low affinity autoreactive TCR specificities for the treatment of ongoing autoimmune disease. Finally, we will begin to translate these murine observations to human pMHCII-CAR T cells and assess their potential utility in a relevant human autoimmune CNS disease.