Overcoming skin rejection in composite tissue allotransplantation.

The application of composite tissue techniques is constrained by the susceptibility of skin to rejection. The aim of this thesis is to improve our understanding of skin rejection and find ways to avoid it, in order to enable expansion of the application of composite tissue transplantation techniques. The first part of the thesis explores the consequences and mechanism of skin rejection in rat models. These studies indicate that in the event of allograft failure, there is minimal damage to the vascular pedicle of a composite tissue allotransplant, even after full rejection, making retransplantation possible. Furthermore, there is only mild damage to the recipient tissues, indicating that the second transplant would not be limited in form or function by recipient tissue bed damage. Finally, the studies indicate that there are significant differences between the mechanism of rejection of skin in composite tissue transplants and conventional skin grafts. This means that much of the historical data relating to skin graft rejection is not necessarily relevant to composite tissue allotransplantation. The second part of the thesis uses swine models to explore ways to overcome skin rejection while avoiding the toxicity of chronic systemic immunosuppression, through tolerance induction, and site specific therapy. Previous experience in organ and composite tissue allotransplantation models are analysed to develop the hypothesis that high-level chimeras are tolerant to vascularised skin allotransplants. In utero and adult chimerism induction models are then used in an attempt to attain moderate-level chimeras. A vascularised skin allotransplant model is developed. Finally, the hypothesis is confirmed with the transplantation of a vascularised skin allotransplant on to moderate-level chimeras with the achievement of tolerance. In addition, site-specific therapy is used in an attempt to avoid the side-effects of chronic high-dose systemic immunosuppression. This led to prolongation of skin survival, but eventual skin rejection