Future improvements in immunosuppression for clinical organ transplantation will need to be based on a biological approach to donor- specific immunosuppression to increase the safety and success of organ transplants. Antigen specific immunosuppression directed at the major histocompatibility antigens of the transplant donor will need to be designed to suppress the action of the lymphocyte clones responsible for rejection of the particular graft the patient receives. To date, donor- specific immunosuppression has been achieved in certain animal models and partially achieved with donor-specific transfusions in human kidney transplant recipients. The application of specific immunosuppression has been limited by 1) availability of donor MHC antigens; 2) lack of a continuous supply of donor MHC antigen; 3) poor understanding of the optimal form of donor antigen (membrane bound versus secreted antigen, monomeric versus multimeric antigen); and 4) an incomplete understanding of the ideal microenvironment for antigen presentation to favor the induction of unresponsiveness. Due to recent developments in gene transfer techniques, MHC antigen availability has been dramatically increased in potential both by in vitro and in vivo MHC gene transfer to myocytes. A continuous in vivo supply of donor MHC antigen may be possible. By genetically altering the DNA encoding the MHC Class I antigen, it is possible to alter the form of MHC antigen.
The aims of the current proposal are to evaluate the immune response to MHC Class I antigen expressed as a result of gene transfer into myocytes. The antibody and T cell response as well as hepatic and cardiac allograft survival following MHC gene transfer will be evaluated. The time course of MHC gene expression following in vivo transfer will be evaluated. The goal of this work will be to develop a means of inducing specific unresponsiveness using MHC gene transfer. Variables studied will include 1) the route of administration; 2) the dose administered; 3) the timing of administration; 4) the form of the gene injected; and 5) the organ transplanted, i.e., liver versus heart. The ultimate goal of this work is to apply gene transfer techniques to development of specific immunosuppression which is clinically applicable to increasing the safety and success of organ transplantation.
|Knechtle, S J; Wang, J; Graeb, C et al. (1997) Direct MHC class I complementary DNA transfer to thymus induces donor-specific unresponsiveness, which involves multiple immunologic mechanisms. J Immunol 159:152-8|
|Knechtle, S J; Wang, J; Jiao, S et al. (1994) Induction of specific tolerance by intrathymic injection of recipient muscle cells transfected with donor class I major histocompatibility complex. Transplantation 57:990-6|