Abstract
881 Previous studies suggest that liver allografts can provide protection for other transplanted organs. In this respect heart allograft rejection can be prevented, and even reversed, with a liver transplant from the same donor. One possible explanation for this phenomenon is that hepatocytes produce relatively large amounts of potentially immunosuppressive soluble MHC class I antigen (Ag). In support of this theory we have recently shown that hepatocyte-secreted, soluble, allogeneic-MHC class I Ag downregulates both cytotoxic and helper T lymphocyte responses in vivo. In the present study we examined the potential immunosuppressive effects of hepatocyte-secreted donor-MHC Ag in a rat heart allograft model. Hepatocytes were obtained by collagenase digestion of a Lewis (RT11) liver. Cells were cultured and subsequently transfected by lipofection to express the soluble donor-MHC class I Ag, RT1.Aa (plasmid: pcRQ.B3). One day prior to ACI (RT1a) heterotopic heart allografting, Lewis recipients were injected with 1 × 107 pcRQ.B3-transfected hepatocytes via the spleen. Controls did not receive hepatocytes or were injected with hepatocytes transfected with a gene encoding firefly-luciferase (pCMVLux). All animals received a short-course of cyclosporin A (10 mg/kg/day, i.p.) on days 0 to +7, relative to heart transplantation. Graft survival results showed that recipients injected with hepatocytes expressing soluble donor-MHC class I Ag experienced a prolongation of ACI heart allograft survival, when compared to control. (Table)TableThese results suggest that the immunosuppressive effects of a single mismatched soluble donor-MHC class I Ag are sufficiently potent to promote heart allograft survival in a fully MHC-disparate, high-responder, rat-strain combination. This is one of the first steps in the development of a gene transfer-based system to deliver soluble donor-MHC class I molecules to organ transplant recipients. We are currently refining this gene transfer system to allow for more prolonged soluble donor-MHC expression in vivo, which we predict is a critical factor to provide for longer immunologic protection of heart allografts. Also, it is likely that delivery of a single type of mismatched donor-MHC Ag will be more effective between strain combinations where the MHC is not completely different. In summary, these results provide incentive to determine the full potential of soluble donor-MHC class I gene therapy in organ transplantation.
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