Costimulation Blockade in Experimental Transplantation

Abstract: Transplantation is the only cure for end-stage organ failure. With the transplantation follows the need for continuous treatment with immunosuppressive agents for as long as the graft functions, which entails major side effects. Less toxic treatments are therefore in great demand. Preferably, the treatment should also be limited in time. The ultimate solution would be induction of tolerance to the graft. To achieve this, interference with T cell activation signals, especially blockade of costimulation molecules, has been exploited. In this thesis, blockade of costimulatory molecules in different combinations has been tested for its capacity to prolong survival of grafts of different origins in a rodent model. The mechanisms of action have also been investigated. Blockade of the CD28-B7 and ICAM-LFA-1 pathways acted synergistically in inhibiting T cell proliferation and prolonging survival of transplanted heart and skin grafts. Prolonged blockade of ICAM-LFA-1 ligation was of benefit, while on the other hand, prolonged blockade of CD28-B7 resulted in accelerated rejection of secondary skin transplants. The treatment did not induce linked suppression or dominant tolerance, in that secondary transplants of either the same tissue origin or other tissue origin were eventually rejected in the majority of cases. Moreover, a secondary transplant evoked an inflammatory reaction leading to rejection changes in the first transplant, as judged by histological examination. Combined blockade of CD40-CD40L and CD28-B7 pathways allowed survival of islet grafts for more than 100 days and on histological examination of these grafts no cellular reaction against the graft could be detected. The addition of anti-LFA-1 did not confer any benefit. Costimulation blockade was not dependent on the presence of CD4+CD25+ T cells or T cell derived IL-10 in order to mediate graft acceptance. CD4+CD25+ T cells could develop from CD4+CD25- T cells in the periphery in animals treated with costimulation blockade. Hence, a combination of two or three agents blocking different costimulatory pathways is more effective in prolonging survival of transplanted grafts than the use of either agent alone.