Effect of CpG Depletion of Vector Genome on CD8(+) T Cell Responses in AAV Gene Therapy.
Effect of CpG Depletion of Vector Genome on CD8(+) T Cell Responses in AAV Gene Therapy.
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AAV 基因治疗中载体基因组 CpG 缺失对 CD8(+) T 细胞反应的影响。
DOI：
10.3389/fimmu.2021.672449
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发表时间：
2021
影响因子：
7.3
通讯作者：
Herzog RW
中科院分区：
文献类型：
--
作者：
Bertolini TB;Shirley JL;Zolotukhin I;Li X;Kaisho T;Xiao W;Kumar SRP;Herzog RW
腺相关病毒（AAV）载体已成为体内基因替代治疗的首选平台，是治疗血友病等单基因疾病最有前途的策略之一。然而，对基因转移的免疫反应阻碍了人类基因治疗在临床试验中的应用。在过去的十年中，人们已经清楚地认识到先天免疫识别为诱导针对载体或转基因产物的抗原特异性反应提供了信号。特别是，在浆细胞样树突状细胞（pDCs）中，TLR9对载体DNA基因组的识别被认为是一个关键因素。来自临床试验和临床前研究的数据表明，载体基因组中的CpG基序是免疫反应的驱动因素，特别是CD8+ T细胞激活。在这里，我们证明了AAV衣壳特异性CD8+ T细胞的交叉启动依赖于XCR1+树突状细胞（这可能是与pDCs合作激活CD8+ T细胞的主要交叉呈递细胞），并且可以通过消除载体基因组中的CpG基序来最小化。此外，与传统的CpG+载体（由天然序列组成）相比，表达人凝血因子IX的CpG缺失载体在血友病B小鼠肌肉内基因转移时显着减少（尽管不是完全消除）CD8+ T细胞浸润，从而更好地保存转导的肌纤维。因此，这种脱免疫策略有助于降低CD8+ T细胞对衣壳或转基因产物的潜在反应。然而，CpG消耗对针对衣壳或转基因产物的抗体反应的影响很小，这似乎在很大程度上独立于CpG基序。
Adeno associated viral (AAV) vectors have emerged as a preferred platform for in vivo gene replacement therapy and represent one of the most promising strategies to treat monogenetic disorders such as hemophilia. However, immune responses to gene transfer have hampered human gene therapy in clinical trials. Over the past decade, it has become clear that innate immune recognition provides signals for the induction of antigen-specific responses against vector or transgene product. In particular, TLR9 recognition of the vector’s DNA genome in plasmacytoid dendritic cells (pDCs) has been identified as a key factor. Data from clinical trials and pre-clinical studies implement CpG motifs in the vector genome as drivers of immune responses, especially of CD8+ T cell activation. Here, we demonstrate that cross-priming of AAV capsid-specific CD8+ T cells depends on XCR1+ dendritic cells (which are likely the main cross-presenting cell that cooperates with pDCs to activate CD8+ T cells) and can be minimized by the elimination of CpG motifs in the vector genome. Further, a CpG-depleted vector expressing human coagulation factor IX showed markedly reduced (albeit not entirely eliminated) CD8+ T cell infiltration upon intramuscular gene transfer in hemophilia B mice when compared to conventional CpG+ vector (comprised of native sequences), resulting in better preservation of transduced muscle fibers. Therefore, this deimmunization strategy is helpful in reducing the potential for CD8+ T cell responses to capsid or transgene product. However, CpG depletion had minimal effects on antibody responses against capsid or transgene product, which appear to be largely independent of CpG motifs.
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影响因子：
64.5
作者：
Eickhoff S;Brewitz A;Gerner MY;Klauschen F;Komander K;Hemmi H;Garbi N;Kaisho T;Germain RN;Kastenmüller W
通讯作者：
Kastenmüller W
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
TLR9 激活 CpG-B ODN（而非 TLR7 激动剂）在肌肉基因转移中触发针对因子 IX 的抗体形成。
影响因子：
--
作者：
Butterfield, John S. S.;Biswas, Moanaro;Herzog, Roland W.
通讯作者：
Herzog, Roland W.
影响因子：
4.4
作者：
Crozat, Karine;Tamoutounour, Samira;Dalod, Marc
通讯作者：
Dalod, Marc
影响因子：
20.3
作者：
Martino, Ashley T.;Basner-Tschakarjan, Etiena;Herzog, Roland W.
通讯作者：
Herzog, Roland W.