AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes
| Autor: | Federico Mingozzi, Daniel J. Hui, Hildegund C.J. Ertl, Shyrie C Edmonson, Rodney M. Camire, Etiena Basner-Tschakarjan, Lacramioara Ivanciu, Katherine A. High, Gregory M. Podsakoff, Gary C. Pien |
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| Rok vydání: | 2015 |
| Předmět: |
lcsh:QH426-470
viruses Human leukocyte antigen Major histocompatibility complex Epitope Virus Article 03 medical and health sciences 0302 clinical medicine Immune system Genetics Cytotoxic T cell Medicine Vector (molecular biology) lcsh:QH573-671 Molecular Biology 030304 developmental biology 0303 health sciences biology business.industry lcsh:Cytology Virology 3. Good health lcsh:Genetics Capsid 030220 oncology & carcinogenesis Immunology biology.protein Molecular Medicine business |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 2, Iss, Pp-(2015) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| DOI: | 10.1038/mtm.2015.29 |
| Popis: | Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses. We were able to identify immunodominant major histocompatibility complex (MHC) class I epitopes for common human leukocyte antigen (HLA) types by using spleens isolated from subjects undergoing splenectomy for non-malignant indications as a source of large numbers of lymphocytes and restimulating them with single AAV capsid peptides in vitro. Further experiments confirmed that these epitopes are naturally processed and functionally relevant. The design of more effective and less immunogenic AAV vectors, and precise immune monitoring of vector-infused subjects, are facilitated by these findings. |
| Databáze: | OpenAIRE |
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