Gene Transfer of Transforming Growth Factor-β1 Prolongs Murine Cardiac Allograft Survival by Inhibiting Cell-Mediated Immunity

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Abstract
Delivery of immunosuppressants directly to allografts using gene transfer and gene therapy approaches may inhibit immune activation while avoiding the systemic toxicity of conventional immunosuppression. Cardiac grafts from allogeneic (C57BL/6, H-2b) donors were transplanted into CBA/J (H-2k) recipients in a heterotopic, nonvascularized model. pSVTGF-β1, a plasmid encoding murine transforming growth factor-β1 (TGF-β1) under the control of an SV40 promoter, was directly injected into grafts at surgery and prolonged survival from 12.0 ± 0.7 to 25.1 ± 2.1 days (p < 0.001) in a dose-dependent manner. Plasmid gene transfer-induced immunosuppression was localized to the area of the graft because plasmid injected remote from the graft did not prolong allograft survival and systemic immunity was not influenced by local gene transfer. Limiting dilution analysis of graft-infiltrating cells demonstrated that gene transfer reduced the precursor frequency of donor-specific cytotoxic T lymphocytes (CTL) and activated and total interleukin-2 (IL-2) producing helper T lymphocytes (HTL) in graft-infiltrating cells, whereas CTL generation and HTL precursor frequency in splenic lymphocytes were not altered. Additional data revealed that gene transfer inhibited the priming of TH0 cells and the conversion of primed TH1 cells to activated cells without the participation of TH2 suppressors. These data demonstrate that gene transfer of plasmid DNA encoding TGF-β1 in vivo suppresses local T cell immunity, which prolongs allograft survival. Transforming growth factor-β1 (TGF-β1) is an immunosuppressive cytokine that negatively regulates a variety of immune responses. The inhibition of host immune responses by TGF-β1 could be an important therapeutic adjunct for the prevention of transplant rejection. Utilizing techniques of gene transfer, we previously demonstrated that plasmid mediated transfer of TGF-β1 could prolong allograft survival. In this study, we demonstrate that TGF-β1 gene transfer-induced immunosuppression is localized only to the area of the graft Prolongation of graft survival is associated with inhibition of donor-specific cytotoxic T cell and interleukin-2 (IL-2) producing helper T cell function in graft-infiltrating cells, the priming of TH0 cells, and the conversion of primed TH1 cells to activated cells without the participation of TH2 suppressors. These data demonstrate that gene transfer of plasmid DNA encoding TGF-β1 in vivo suppresses local T cell immunity, which prolongs allograft survival.