Rebecca Xicluna, Allan Avenel, Céline Vandamme, Marie Devaux, Nicolas Jaulin, Célia Couzinié, Johanne Le Duff, Alicia Charrier, Mickaël Guilbaud, Oumeya Adjali, Gwladys Gernoux
{"title":"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。","authors":"Rebecca Xicluna, Allan Avenel, Céline Vandamme, Marie Devaux, Nicolas Jaulin, Célia Couzinié, Johanne Le Duff, Alicia Charrier, Mickaël Guilbaud, Oumeya Adjali, Gwladys Gernoux","doi":"10.1089/hum.2023.225","DOIUrl":null,"url":null,"abstract":"<p><p>Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors for <i>in vivo</i> 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.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"355-364"},"PeriodicalIF":3.9000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Prevalence Study of Cellular Capsid-Specific Immune Responses to AAV2, 4, 5, 8, 9, and rh10 in Healthy Donors.\",\"authors\":\"Rebecca Xicluna, Allan Avenel, Céline Vandamme, Marie Devaux, Nicolas Jaulin, Célia Couzinié, Johanne Le Duff, Alicia Charrier, Mickaël Guilbaud, Oumeya Adjali, Gwladys Gernoux\",\"doi\":\"10.1089/hum.2023.225\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors for <i>in vivo</i> 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. 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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.
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.