Antibody inhibitors pose an ongoing challenge to the treatment of subjects with inherited protein deficiency disorders, limiting the efficacy of both protein replacement therapy and corrective gene therapy. Beyond their central role as producers of serum antibody, B cells also exhibit many unique properties that could be exploited in cell therapy applications, notably including antigen-specific recognition and the linked capacity for antigen presentation. Here we employed CRISPR-Cas9 to demonstrate that ex vivo antigen-primed Blimp1-knockout “decoy” B cells, incapable of differentiation into plasma cells, participated in and downregulated host antigen-specific humoral responses after adoptive transfer. Following ex vivo antigen pulse, adoptively transferred high-affinity antigen-specific decoy B cells were diverted into germinal centers en masse, thereby reducing participation by endogenous antigen-specific B cells in T-dependent humoral responses and suppressing both cognate and linked antigen-specific immunoglobulin (Ig)G following immunization with conjugated antigen. This effect was dose-dependent and, importantly, did not impact concurrent unrelated antibody responses. We demonstrated the therapeutic potential of this approach by treating factor VIII (FVIII)-knockout mice with antigen-pulsed decoy B cells prior to immunization with an FVIII conjugate protein, thereby blunting the production of serum FVIII-specific IgG by an order of magnitude as well as reducing the proportion of animals exhibiting functional FVIII inhibition by 6-fold.

中文翻译：

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用工程化的“诱饵”B 细胞减弱特异性 T 依赖性抗体反应


抗体抑制剂对遗传性蛋白质缺乏症患者的治疗构成了持续的挑战，限制了蛋白质替代疗法和纠正基因疗法的疗效。除了作为血清抗体生产者的核心作用外，B 细胞还表现出许多可在细胞治疗应用中利用的独特特性，特别是包括抗原特异性识别和抗原呈递的相关能力。在这里，我们使用 CRISPR-Cas9 来证明离 体抗原引发的 Blimp1 敲除“诱饵”B 细胞，无法分化为浆细胞，参与并下调过继转移后宿主抗原特异性体液反应。在离 体抗原脉冲后，过继转移的高亲和力抗原特异性诱饵 B 细胞被集体转移到生发中心，从而减少内源性抗原特异性 B 细胞对 T 依赖性体液反应的参与，并抑制同源和连接的抗原特异性免疫球蛋白 （Ig）G在用缀合抗原免疫后。这种效应是剂量依赖性的，重要的是，不会影响并发的不相关抗体反应。我们通过在用 FVIII 偶联蛋白免疫之前用抗原脉冲诱饵 B 细胞处理因子 VIII （FVIII） 敲除小鼠来证明这种方法的治疗潜力，从而将血清 FVIII 特异性 IgG 的产生减弱一个数量级，并将表现出功能性 FVIII 抑制的动物的比例降低 6 倍。