Immunosuppresive properties of new potential drugs in transplantation

Abstract: Transplantation of vital organs is today a widely used treatment when failure of the organ is a fact. To prevent rejection immunosuppresive treatment must be maintained lifelong, unless transplantation is perfomed between identical twins. Many immunosuppresive agents introduced in clinical practice have been benificial in improving graft survival rates, but adverse effects remains a huge problem together with late loss of grafts. There is a need for improved medical strategies. In search for immunosuppressive drugs, monocarboxylate transporter (MCT1) inhibitors were identified and in vitro studies revealed a marked inhibibition of the immune response by the compound. Blockage of costimulatory pathways is another alternative that has been explored during the past few years. The aim of this study was to evaluate the immunological response in terms of graft survival, histological evidence of inflammatory response, toxicity and drug administration of costimulatory antibodies and the new immunomodulatory compounds, MCT1 inhibitors, in cardiac-, skin- and pancreatic islet transplantation models in rodents. The results show that in costimulatory blockade the combination of two or three antibodies, anti- CD40L, CTLA4Ig and anti-LFA-1, resulted in indefinite graft survival of allogenic islets transplanted in mice and that the combination of anti-CD40L and CTLA4Ig totally prevented the rejection and histological signs of islet destruction. The new compounds, MCT1 inhibitors, did induce indefinite graft survival in allograft transplantation models in the rat. The MCT1 inhibitor AR-C117977 showed the best graft survival rates out of seven different analogues and was therefore evaluated in more challenging models like skin- and cardiac xenotransplantation. The limitations for this compound were transplantation to rats already sensitised with preformed antibodies. We could still demonstrate, in addition to suppression of T-cell proliferation, that this compound also had a suppressive effect on Bcells and antibody production. In conclusion MCT1 inhibitors demonstrated promising results of immunosuppressive properties and graft survival in different transplantation models. Further developments of MCT1 inhibition have the potential to give a positive contribution to the treatment used in clinic practice in transplanted patients in the future.