B cell-targeted CAR-T 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 自身免疫性疾病如多发性硬化症（MS）。这促使了对嵌合抗原的探索 受体（CAR）T细胞利用以特异性消除自身反应性细胞。B细胞对MS的贡献 和相关疾病的治疗在一定程度上是通过B细胞耗竭疗法的成功来认识的。然而，B的耗尽 用于神经免疫疾病的细胞的选择性不足以避免与非特异性免疫相关的安全性问题。 B细胞耗竭，包括免疫抑制和感染。因此，我们寻求开发CAR T细胞， 抗原特异性自身反应性B细胞，使用B细胞依赖型实验性自身免疫 脑脊髓炎（EAE），与炎性脱髓鞘疾病相关的动物模型， 在初步研究中，我们已经创建了一个独特的CAR T版本， 其中肽MHCII（pMHCII）与信号传导结构域融合以识别特异性T细胞的细胞 受体（TCR）。我们证明，这些pMHCII-CAR T细胞特异性地识别免疫应答中的同源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性B细胞 用于治疗B细胞依赖性EAE的两个目的。在目标1中，我们将优化生存， 靶向髓鞘少突胶质细胞糖蛋白（MOG）特异性B细胞的表达CAR T细胞的杀伤作用 预防和治疗EAE。在目标2中，我们将利用靶向MOG特异性的pMHCII-CAR T细胞， TCR与靶向EAE中自身反应性B细胞的MOG-CAR T细胞组合。总而言之，我们的建议 研究将探索CAR T细胞方法用于治疗CNS自身免疫的潜力， 解决了如何最佳地消除TCR和BCR特异性而不导致 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.