Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells.
Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells.
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DOI：
10.1016/j.omtm.2021.10.010
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发表时间：
2021-12-10
期刊：
影响因子：
--
通讯作者：
Keeler AM
中科院分区：
文献类型：
--
作者：
Arjomandnejad M;Sylvia K;Blackwood M;Nixon T;Tang Q;Muhuri M;Gruntman AM;Gao G;Flotte TR;Keeler AM
对腺相关病毒 (AAV) 衣壳的免疫反应限制了 AAV 基因治疗的治疗潜力。在此，我们通过生成 AAV 衣壳特异性嵌合抗原受体 (AAV-CAR) T 细胞来模拟临床免疫反应。然后，我们使用 AAV-CAR 调节性 T 细胞 (Treg) 调节对 AAV 衣壳的免疫反应。 AAV-CAR Tregs 在体外表现出表型 Treg 表面标志物表达，以及效应 T 细胞增殖和细胞毒性的功能抑制。在小鼠模型中，尽管存在抗体反应，AAV-CAR Tregs仍介导免疫原性衣壳的持续转基因表达，产生免疫抑制细胞因子并减少组织炎症。 AAV-CAR Tregs 还能够旁观者抑制对免疫原性转基因的免疫反应，同样介导持续的转基因表达、产生免疫抑制细胞因子并减少组织浸润。总而言之，AAV-CAR T 细胞和 AAV-CAR Tregs 是强大的定向免疫抑制工具，可模拟和调节局部环境中对 AAV 衣壳和转基因的免疫反应。我们在此利用 AAV-CAR Tregs 来创建抑制衣壳和 AAV 传递的转基因反应的耐受环境，从而允许转导细胞持续表达转基因。这种诱导的局部免疫耐受最终可能比全身性广谱免疫抑制在临床上更安全。
Immune responses to adeno-associated virus (AAV) capsids limit the therapeutic potential of AAV gene therapy. Herein, we model clinical immune responses by generating AAV capsid-specific chimeric antigen receptor (AAV-CAR) T cells. We then modulate immune responses to AAV capsid with AAV-CAR regulatory T cells (Tregs). AAV-CAR Tregs in vitro display phenotypical Treg surface marker expression, and functional suppression of effector T cell proliferation and cytotoxicity. In mouse models, AAV-CAR Tregs mediated continued transgene expression from an immunogenic capsid, despite antibody responses, produced immunosuppressive cytokines, and decreased tissue inflammation. AAV-CAR Tregs are also able to bystander suppress immune responses to immunogenic transgenes similarly mediating continued transgene expression, producing immunosuppressive cytokines, and reducing tissue infiltration. Taken together, AAV-CAR T cells and AAV-CAR Tregs are directed and powerful immunosuppressive tools to model and modulate immune responses to AAV capsids and transgenes in the local environment. We herein utilized AAV-CAR Tregs to create tolerogenic environments suppressing both capsid and AAV-delivered transgene responses allowing for continued transgene expression from transduced cells. This induced local immune tolerance may ultimately be safer clinically than systemic, broad-spectrum immune suppression.
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影响因子：
--
作者：
Elkord E;Abd Al Samid M;Chaudhary B
通讯作者：
Chaudhary B
影响因子：
17.1
作者：
Chan YK;Wang SK;Chu CJ;Copland DA;Letizia AJ;Costa Verdera H;Chiang JJ;Sethi M;Wang MK;Neidermyer WJ Jr;Chan Y;Lim ET;Graveline AR;Sanchez M;Boyd RF;Vihtelic TS;Inciong RGCO;Slain JM;Alphonse PJ;Xue Y;Robinson-McCarthy LR;Tam JM;Jabbar MH;Sahu B;Adeniran JF;Muhuri M;Tai PWL;Xie J;Krause TB;Vernet A;Pezone M;Xiao R;Liu T;Wang W;Kaplan HJ;Gao G;Dick AD;Mingozzi F;McCall MA;Cepko CL;Church GM
通讯作者：
Church GM
影响因子：
4.2
作者：
Flanigan, Kevin M.;Campbell, Katie;Mendell, Jerry R.
通讯作者：
Mendell, Jerry R.
影响因子：
4.2
作者：
Ferreira, Valerie;Twisk, Jaap;Gaudet, Daniel
通讯作者：
Gaudet, Daniel
DOI：
10.1073/pnas.0508685103
发表时间：
2006-03-21
影响因子：
11.1
作者：
Dobrzynski, E;Fitzgerald, JC;Herzog, RW
通讯作者：
Herzog, RW