Improved Immunological Tolerance Following Combination Therapy with CTLA-4/Ig and AAV-Mediated PD-L1/2 Muscle Gene Transfer.
Improved Immunological Tolerance Following Combination Therapy with CTLA-4/Ig and AAV-Mediated PD-L1/2 Muscle Gene Transfer.
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DOI：
10.3389/fmicb.2011.00199
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发表时间：
2011
影响因子：
5.2
通讯作者：
Boyer O
中科院分区：
文献类型：
--
作者：
Adriouch S;Franck E;Drouot L;Bonneau C;Jolinon N;Salvetti A;Boyer O
最初被认为是非免疫原性的，重组AAV已经成为治疗单基因疾病的有效载体候选物。然而，现在清楚的是，它们诱导针对转基因产物的有效免疫应答，这可导致转导细胞的破坏。因此，开发策略以规避这些免疫应答并促进转基因治疗蛋白的长期表达是基因治疗中的主要挑战。我们在此评估了一种抑制肌肉基因转移后不期望的免疫激活的策略，该策略通过施用CTLA-4/IG来阻断免疫引发期间早期所需的共刺激信号，并通过使用PD-1配体的基因转移来抑制组织部位处的T细胞功能。我们提供了原理证明，这种联合免疫调节疗法靶向免疫应答的两个非冗余检查点，即，启动和效应子功能，可以改善转导细胞在实验环境中的持久性，其中细胞毒性T细胞逃避初始阻断。因此，CTLA-4/IG加PD-L1/2联合治疗代表了绕过针对转基因产物的免疫应答瓶颈的候选方法。
Initially thought as being non-immunogenic, recombinant AAVs have emerged as efficient vector candidates for treating monogenic diseases. It is now clear however that they induce potent immune responses against transgene products which can lead to destruction of transduced cells. Therefore, developing strategies to circumvent these immune responses and facilitate long-term expression of transgenic therapeutic proteins is a main challenge in gene therapy. We evaluated herein a strategy to inhibit the undesirable immune activation that follows muscle gene transfer by administration of CTLA-4/Ig to block the costimulatory signals required early during immune priming and by using gene transfer of PD-1 ligands to inhibit T cell functions at the tissue sites. We provide the proof of principle that this combination immunoregulatory therapy targeting two non-redundant checkpoints of the immune response, i.e., priming and effector functions, can improve persistence of transduced cells in experimental settings where cytotoxic T cells escape initial blockade. Therefore, CTLA-4/Ig plus PD-L1/2 combination therapy represents a candidate approach to circumvent the bottleneck of immune responses directed toward transgene products.
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DOI：
10.1073/pnas.93.24.14082
发表时间：
1996-11-26
影响因子：
11.1
作者：
Kessler, PD;Podsakoff, GM;Byrne, BJ
通讯作者：
Byrne, BJ
影响因子：
30.5
作者：
Latchman, Y;Wood, CR;Freeman, GJ
通讯作者：
Freeman, GJ
影响因子：
30.5
作者：
Grohmann, U;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
4.4
作者：
Du, Lanying;Zhao, Guangyu;Zheng, Bo-Jian
通讯作者：
Zheng, Bo-Jian
影响因子：
8.6
作者：
Brockstedt, DG;Podsakoff, GM;Engleman, EG
通讯作者：
Engleman, EG