DNA-liposome versus adenoviral mediated gene transfer of transforming growth factor beta 1 in vascularized cardiac allografts: Differential sensitivity of CD4+and CD8+T cells to transforming growth factor beta 1

We have developed a model of transforming growth factor (TGF)beta1 gene tra nsfer into mouse vascularized cardiac allografts to study the use of gene t ransfer as an immunosuppressive therapy in transplantation. Donor hearts we re perfused with either DNA-liposome complexes or adenoviral vectors that e ncode the active form of human TGF beta1. DNA-liposome mediated transfectio n prolonged allograft survival in approximately two-thirds of transplant re cipients, while adenoviral delivery of TGF beta1 was not protective. Protec tive TGF beta1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGF beta1 gene transfer were overridden by exogenous interleukin-la admini stration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinc t sensitivities to TGF beta1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfect ed with either DNA-liposome complexes or adenoviral vectors. Transgene expr ession persisted for at least 60 days, and Th1 responses were not detectabl e until CD8+ T cells repopulated the periphery. However, long-term transfec ted allografts appeared to exhibit exacerbated fibrosis and neointimal deve lopment. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGF beta1 alone is not sufficient to induce fibrosis of the grafts. Collectivel y, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning r egimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.