Prevention of viral vector immune responses in gene therapy

Summary: Prevention of viral vector immune responses in gene therapy The main obstacle to viral vector mediated gene therapy remains the elicitation of an immune response to the vector, resulting in clearance of the transgene and resistance to further transgene-based therapy. Specific antibody production contributes to such immune responses. In this study, we developed a novel methodology to control the antigen-specific immune responses towards adenovirus vectors. We demonstrated that antigen-specific responses can be prevented by administration of peptides encompassing T cell epitopes and including a motif carrying an oxido-reductase activity. A single class II-restricted epitope of Adenovirus 5 (Ad5) vector hexon-6 capsid protein containing a CxxC motif was used in an attempt to prevent specific antibody production to Ad5 vectors. We demonstrated that such immunization carried out prior to intravenous administration of Ad5 vectors prevented antibody production to the ensemble of Ad5 vector proteins in both BALB/c and C57BL/6 mice. The antibody response to Ad5 was dependent on innate immune activation, seemingly involving NKT cells. We observed that immunization with a class II-restricted Ad5 epitope prevented such NKT cell activation. Increased transduction and prolonged transgene expression resulted from such immunization, providing a simple protocol for improving gene therapy. In addition, the in vitro-derived CD4+ T cells stimulated with the MHC class II-restricted hexon epitope carried cytolytic properties exerted over APC with which a cognate synapse had been formed. In conclusion, the induction of MHC class II-restricted antigen-specific cytolytic CD4+ T cells carries the hope to achieve antigen-specific immunosuppression that may benefit a range of clinical applications involving gene therapy.status: publishe