Gene transfer for facilitating transplantation

Transplantation has shown significant improvement over the last two to three decades. This improvement is mostly due to the development of the immunosuppressive agents reflecting the progress in understanding the cellular and molecular mechanisms that mediate transplant rejection. Although the use of immunosuppressive agents has markedly improved the survival of transplants, transplantation still faces various problems. Strategies to solve these problems have been developed using various approaches.; Gene transfer may facilitate the induction of immunological tolerance and protect the transplant locally against the host's immune response. Furthermore, gene transfer allows for the possibility of delivering molecules with immunomodulating activity to the donor organ, which may either reduce graft immunogenicity or protect the graft from the host immune system. Gene transfer has several potential advantages over systemic administration of delivery of these immunosuppressive agents. Secreted proteins produced by the graft after gene transfer could potentially produce local immunosuppressive effects, avoiding generalized immunosuppression.; In Chapter 1, I have tested various immunosuppressive molecules for their use in transplantation. For this analysis, I have used an in vivo tumor model that is normally rejected by the immune system upon engraftment into immunocompetent mice. However, they can grow tumors in irradiated, immunodefficient hosts, or by expressing immunosuppressive molecules. Many groups have been working on different immunosuppressive molecules to block the immune reaction against the graft. I have compared four molecules that were used in different studies to prolong the survival of the graft.; In Chapter 2, I have examined the consequences of over-expression of anti-apoptotic genes and their use in transplantation. For this study, I used a tumor model that reflects the in vivo immunologic environment. This model utilizes tumor cell lines that are normally rejected by the immune system upon transplantation into allogeneic mice.; In Chapter 3, I have used myoblast transplantation to compare various immunosuppressive and anti-apoptotic molecules that were tested in Chapters 1 and 2. To determine their outcome in a clinically relevant transplantation setting, I adapted myoblast transfer as an application model for transplantation.