Key result
In vitro restimulation of lymphocytes from human spleens with single AAV capsid peptides identified naturally processed and functionally relevant immunodominant MHC class I epitopes.
The identification of highly conserved AAV capsid CD8+ T-cell epitopes facilitates the design of less immunogenic AAV vectors and precise immune monitoring in gene therapy.
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May guide less immunogenic AAV vector design; leaves open clinical utility of epitope monitoring.
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.
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Hui et al. (2015) studied Subjects undergoing splenectomy for non-malignant indications. Single AAV capsid peptides in vitro was evaluated on Identification of immunodominant MHC class I epitopes for common HLA types. In vitro restimulation of lymphocytes from human spleens with single AAV capsid peptides identified naturally processed and functionally relevant immunodominant MHC class I epitopes.
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