Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression
| Autor: | Roberto Calcedo, James M. Wilson, Maigan A. Hulme, Lee P. Richman, Brenna Carey, Noel G. McElvaney, Guo-jie Ye, Ann Dongtao Fu, Mark L. Brantly, Todd M. Brusko, Margaret Humphries, Jeffrey D. Chulay, Qiushi Tang, Anthony T. Yachnis, Terence R. Flotte, Christian Mueller, Martha Campbell-Thompson, Farshid N. Rouhani, Bruce C. Trapnell, Suryanarayan Somanathan, Louis M. Messina, David R. Knop, Robert A. Sandhaus, Robert H. Vonderheide |
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| Rok vydání: | 2013 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities T cell Genetic enhancement viruses Biopsy Receptors Antigen T-Cell alpha-beta Recombinant Fusion Proteins Population Genetic Vectors Biology medicine.disease_cause Lymphocyte Activation Injections Intramuscular T-Lymphocytes Regulatory Immune system Capsid Antigen alpha 1-Antitrypsin Deficiency medicine Humans Vector (molecular biology) Transgenes Gene Rearrangement beta-Chain T-Cell Antigen Receptor education Muscle Skeletal Adeno-associated virus education.field_of_study General Medicine Gene rearrangement Genetic Therapy Dependovirus Clone Cells medicine.anatomical_structure Gene Expression Regulation alpha 1-Antitrypsin Immunology Research Article |
| Zdroj: | The Journal of clinical investigation. 123(12) |
| ISSN: | 1558-8238 |
| Popis: | Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1–AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy. |
| Databáze: | OpenAIRE |
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