Immunosuppresive properties of new potential drugs in transplantation

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.