Systemic protein delivery by muscle-gene transfer is limited by a local immune response

摘要: Adeno-associated viral (AAV) vectors have been successfully used for therapeutic expression of systemic transgene products (such as factor IX or erythropoietin) following in vivo administration to skeletal muscle animal models inherited hematologic disorders. However, an immune response may be initiated if the product represents a neoantigen. Here, we use ovalbumin (OVA) model antigen and demonstrate immune-mediated elimination on muscle-directed AAV-2 gene transfer. Administration competent mice resulted transient OVA expression. Within 10 days, OVA-specific T-helper cells had activated draining lymph nodes, inflammatory ensued, OVA-expressing fibers were destroyed by cytotoxic CD8+ T-cell response. Use muscle-specific promoter did not prevent this Adoptively transferred CD4+ transgenic receptor specific peptide-major histocompatibility complex class II showed antigen-specific, vector dose-dependent proliferation confined nodes AAV-OVA–transduced within 5 days after transfer subsequently participated lymphocytic infiltration transduced muscle. This study documents that local limits sustained secreted protein transfer, finding consequences design clinical protocols.