嵌合抗原受体 T 细胞介导的中枢神经系统自身免疫中的 B 细胞耗竭。
CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity.
机构信息
From the Department of Neurology (S.G., S.A.S., C.S., R.D., S.L.H., M.R.W., S.S.Z.), Weill Institute for Neurosciences, University of California San Francisco, CA; Department of Cellular Molecular Pharmacology (M.S., J.D., W.L.), University of California San Francisco Cell Design Institute, CA; Veterans Affairs Health Care System (R.A.S.), Department of Pathology, Stanford University School of Medicine, CA; Departments of Neurology and Pathology and Immunology (G.F.W.), Washington University in St. Louis, MO; and Chan Zuckerberg Biohub (W.W., J.E.P.), San Francisco, CA.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2023 Jan 19;10(2). doi: 10.1212/NXI.0000000000200080. Print 2023 Mar.
BACKGROUND AND OBJECTIVES
Anti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS.
METHODS
Anti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation.
RESULTS
Clinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone.
DISCUSSION
In contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion.
背景与目的
抗 CD20 单克隆抗体（mAb）B 细胞耗竭是一种非常成功的多发性硬化症（MS）治疗方法。嵌合抗原受体（CAR）-T 细胞以非主要组织相容性复合体（MHC）限制的方式靶向抗原，能够比 mAb 更彻底地穿透组织。然而，先前的一项研究表明，抗 CD19 CAR-T 细胞可能会反常地加剧实验性自身免疫性脑脊髓炎（EAE）疾病。我们在一种依赖 B 细胞的 EAE 模型中测试了抗 CD19 CAR-T 细胞，该模型对类似于 MS 中抗 CD20 mAb 治疗的临床益处的抗 CD20 B 细胞耗竭有反应。
方法
用环磷酰胺（Cy）预处理的 C57BL/6 小鼠中转染抗 CD19 CAR-T 细胞或过度表达绿色荧光蛋白的对照细胞。用重组人（rh）髓鞘少突胶质细胞蛋白（MOG）免疫小鼠，该蛋白以 B 细胞依赖的方式引起 EAE。评估小鼠的 B 细胞耗竭、EAE 的临床和组织学迹象以及免疫调节。
结果
用 Cy 预处理的抗 CD19 CAR-T 细胞或对照细胞治疗的小鼠的临床评分和淋巴细胞浸润减少，但单独用 Cy 治疗的小鼠没有。在用 Cy 预处理的抗 CD19 CAR-T 细胞治疗的小鼠的外周淋巴组织和中枢神经系统中观察到 B 细胞耗竭。在抗 CD19 CAR-T 细胞、对照细胞治疗的动物或单独用 Cy 中，Th1 或 Th17 群体没有差异。
讨论
与先前表明抗 CD19 CAR-T 细胞治疗加剧 EAE 的数据相反，我们观察到抗 CD19 CAR-T 细胞改善了 EAE。此外，抗 CD19 CAR-T 细胞彻底耗尽了外周组织和中枢神经系统中的 B 细胞。然而，临床获益与抗原特异性或 B 细胞耗竭无关。
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