Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle

Skeletal muscle is an attractive target for somatic gene transfer of bothacquired and inherited disorders. Direct injection of adenoviral vectors inthe skeletal muscle leads to recombinant gene expression in a large numberof muscle fibers. Transgene expression has been transient in most organsand associated with substantial inflammation when experiments are performedin adult immune competent mice. In this report, we utilize a variety of invivo and in vitro models of T and B cell function to characterize thenature of the immune response to adenoviral vectors injected into murineskeletal muscle. Cellular immunity dependent on CD4+ and CD8+ T cellscontributes to the loss of recombinant gene expression and the developmentof localized inflammation. Antigen specific activation of T cells occurs toboth viral proteins and the reporter gene beta-galactosidase. Systemiclevels of neutralizing antibody to the capsid proteins of the vector arealso generated. Destructive immune responses responsible for loss oftransgene expression are largely directed against beta-galactosidase inthat transgene expression was stable when beta-galactosidase was eliminatedas a neoantigen in mice transgenic for lacZ. A strategy to prevent thecellular and humoral immunity to this therapy was developed based ontransiently ablating CD4+ T cell activation at the time of vector delivery.Encouraging results were obtained when vector was administered with one ofseveral immune modulating agents including cyclophosphamide, mAb to CD4+cells, and mAb to CD40 ligand. These studies indicate that cellular andhumoral immune responses are elicited in the context of gene therapydirected to skeletal muscle with adenoviral vectors. Transient ablation ofCD4+ T cell activation prevents the effects responses of the CD8+ T and Bcells.