B cell-targeted CAR-T treatment of CNS Autoimmunity

项目总结 在没有全球免疫抑制的情况下，存在着对选择性和抗原特异性免疫治疗的巨大需求 用于自身免疫性疾病，如多发性硬化症(MS)。这促使人们探索嵌合抗原。 受体(CAR)利用T细胞来特异性地消除自身反应细胞。B细胞在多发性硬化症中的作用 相关疾病在一定程度上是通过B细胞耗竭疗法的成功而被认识到的。然而，B的枯竭 神经免疫疾病的细胞选择性不够，不能避免与非特异性疾病相关的安全问题 B细胞耗尽，包括免疫抑制和感染。因此，我们寻求开发CAR T细胞来靶向 使用B细胞依赖版本的实验性自身免疫的抗原特异性、自身反应性B细胞 脑脊髓炎(EAE)是一种与炎性脱髓鞘疾病相关的动物模型 中枢神经系统(CNS)如MS在初步研究中，我们创造了一个独特的CAR T版本 多肽MHCII(PMHCII)与信号域融合以识别特定T细胞的细胞 受体(TCR)。我们证明了这些pMHCII-CAR T细胞特异性地识别同源TCR 体外和体内，并能够限制EAE的严重程度。我们现在寻求开发抗原特异的B细胞 消耗治疗B细胞依赖型EAE有两个目的。在目标1中，我们将优化 髓鞘少突胶质细胞糖蛋白表达的CAR T细胞靶向MOG特异性B细胞的杀伤作用 在预防和治疗EAE方面。在目标2中，我们将利用针对MOG特异性的pMHCII-CAR T细胞 TCRs与MOG-CAR T细胞联合靶向EAE中自身反应性B细胞。总而言之，我们建议的 研究将探索CAR T细胞方法治疗中枢神经系统自身免疫的可能性 解决如何在不导致覆盖的情况下最佳地消除TCR和BCR的特性 免疫抑制。

PROJECT SUMMARY An immense need for selective and antigen-specific immunotherapy without global immunosuppression exists for autoimmune diseases such as multiple sclerosis (MS). This has prompted exploration of chimeric antigen receptor (CAR) T cell utilization to specifically eliminate autoreactive cells. The contribution of B cells to MS and related diseases is recognized in part by the success of B cell depletion therapies. However, depletion of B cells for neuroimmunologic diseases are not selective enough to avoid safety concerns related to non-specific B cell depletion, including immunosuppression and infection. Hence, we seek to develop CAR T cells to target antigen-specific, autoreactive B cells using a B cell-dependent version of experimental autoimmune encephalomyelitis (EAE), an animal model with relevance to inflammatory demyelinating diseases of the central nervous system (CNS) such as MS. In preliminary studies, we have created a unique version of CAR T cells in which peptide MHCII (pMHCII) is fused with signaling domains in order to recognize specific T cell receptors (TCRs). We demonstrate that these pMHCII-CAR T cells specifically recognize a cognate TCR in vitro and in vivo and are capable of limiting EAE severity. We now seek to develop antigen-specific B cell depletion for the treatment of B cell-dependent EAE in two aims. In Aim 1, we will optimize survival of, and killing by, myelin oligodendrocyte glycoprotein (MOG)-expressing CAR T cells targeting MOG-specific B cells in both prevention and treatment of EAE. In Aim 2, we will utilize pMHCII-CAR T cells targeting MOG-specific TCRs in combination with MOG-CAR T cells targeting auto-reactive B cells in EAE. In sum, our proposed studies will explore the potential of a CAR T cell approach for the treatment of CNS autoimmunity by addressing how to optimally eliminate TCR and BCR specificities without leading to blanketed immunosuppression.