GENE-TRANSFER OF TRANSFORMING GROWTH-FACTOR-BETA-1 PROLONGS MURINE CARDIAC ALLOGRAFT SURVIVAL BY INHIBITING CELL-MEDIATED-IMMUNITY

Delivery of immunosuppressants directly to allografts using gene trans fer and gene therapy approaches may inhibit immune activation while av oiding the systemic toxicity of conventional immunosuppression. Cardia c grafts from allogeneic (C57BL/6, H-2(b)) donors were transplanted in to CBA/J (H-2(k)) recipients in a heterotopic, nonvascularized model, pSVTGF-beta 1, a plasmid encoding murine transforming growth factor-be ta 1 (TGF-beta 1) 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, Plasmi d gene transfer-induced immunosuppression was localized to the area of the graft because plasmid injected remote from the graft did not prol ong allograft survival and systemic immunity was not influenced by loc al gene transfer, Limiting dilution analysis of graft-infiltrating cel ls demonstrated that gene transfer reduced the precursor frequency of donor-specific cytotoxic T lymphocytes (CTL) and activated and total i ntepleukin-2 (IL-2) producing helper T lymphocytes (HTL) in graft-infi ltrating cells, whereas CTL generation and HTL precursor frequency in splenic lymphocytes were not altered, Additional data revealed that ge ne transfer inhibited the priming of T(H)0 cells and the conversion of primed T(H)1 cells to activated cells without the participation of T( H)2 suppressors. These data demonstrate that gene transfer of plasmid DNA encoding TGF-beta 1 in vivo suppresses local T cell immunity, whic h prolongs allograft survival.