健康捐献者对 AAV2、4、5、8、9 和 rh10 细胞帽特异性免疫反应的流行率研究。

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2024-05-01 Epub Date: 2024-04-19 DOI:10.1089/hum.2023.225
Rebecca Xicluna, Allan Avenel, Céline Vandamme, Marie Devaux, Nicolas Jaulin, Célia Couzinié, Johanne Le Duff, Alicia Charrier, Mickaël Guilbaud, Oumeya Adjali, Gwladys Gernoux
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引用次数: 0

摘要

重组腺相关病毒(rAAV)载体似乎比以往任何时候都更适合作为体内基因转移的高效病毒载体,欧洲和美国批准的 7 种药物就说明了这一点。尽管如此,人类对 AAV 病毒外壳已有的免疫力仍是成功临床转化的主要限制之一。虽然对 AAV 病毒衣壳已有体液反应的记载,但对 AAV 病毒衣壳特异性 T 细胞反应的普遍性仍有待研究和鉴定。在这项研究中,我们使用标准的 IFNγ ELISpot 检测法调查了一大批健康捐献者中针对 AAV2、4、5、8、9 和 rh10 的 AAV 特异性循环 T 细胞的流行率。我们观察到,对 AAV9 血清型预先存在的细胞免疫力最高,其次是 AAV8、AAV4、AAV2、AAVrh10 和 AAV5,与供体的血清学状态无关。对 T 细胞对两种最常见血清型 8 和 9 的反应进行的深入分析显示,这两种血清型的 IFNγ 分泌主要由 CD8 T 细胞介导。多功能分析显示,AAV8 和 AAV9 的细胞因子谱不同。令人惊讶的是,抗AAV9免疫细胞没有介导IL-2分泌,这表明这些细胞可能是衰竭或终末分化的细胞,而不是细胞毒性T细胞。总之,这些结果表明,对 AAV 的原有免疫力可能因血清型的不同而不同,因此有必要使用多参数监测方法来更好地描述抗头皮细胞免疫力的特征,并预测其在 rAAV 介导的临床试验中的影响。
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Prevalence Study of Cellular Capsid-Specific Immune Responses to AAV2, 4, 5, 8, 9, and rh10 in Healthy Donors.

Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors for in vivo gene transfer as illustrated by the approvals of 7 drugs across Europe and the United States. Nevertheless, preexisting immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas a preexisting humoral response to AAV capsid is well documented, the prevalence of preexisting capsid-specific T cell responses still needs to be studied and characterized. In this study, we investigated the prevalence of AAV-specific circulating T cells toward AAV2, 4, 5, 8, 9, and rh10 in a large cohort of healthy donors using the standard IFNγ ELISpot assay. We observed the highest prevalence of preexisting cellular immunity to AAV9 serotype followed by AAV8, AAV4, AAV2, AAVrh10, and AAV5 independently of the donors' serological status. An in-depth analysis of T cell responses toward the 2 most prevalent serotypes 8 and 9 shows that IFNγ secretion is mainly mediated by CD8 T cells for both serotypes. A polyfunctional analysis reveals different cytokine profiles between AAV8 and AAV9. Surprisingly, no IL-2 secretion was mediated by anti-AAV9 immune cells suggesting that these cells may rather be exhausted or terminally differentiated than cytotoxic T cells. Altogether, these results suggest that preexisting immunity to AAV may vary depending on the serotype and support the necessity of using multiparametric monitoring methods to better characterize anticapsid cellular immunity and foresee its impact in rAAV-mediated clinical trials.

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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
期刊最新文献
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