| Organ transplantation is an ultimate treatment for patients with end-stage diseases of a vital organ. Acute rejection is the main cause of transplantation failure, thus recipient patients must be immunosuppressed in order not to reject their allograft. Ironically, current immunosuppressive protocols can trigger important toxicities on a long-term basis, which represent the second cause of transplantation failure. Research of better drugs and immunosuppressive treatments is indeed necessary. Proliferation assay and organ transplantation in rats are helpful experimental models for the evaluation of new immunosuppressive drugs, and the median effect principle is a good analytical method to determine the type of interaction between two drugs in a combination therapy. The aim of this research project is to evaluate the efficacy of four new immunosuppressive strategies in prevention of acute allograft rejection.; This doctorate thesis includes an introductory part, five original manuscripts (from which, two papers report the same study) divided into four chapters, and a discussion and conclusion section, where particular aspects (methodology, results, perspectives) of each manuscript are discussed and analyzed.; The first study evaluates the effect of the combination therapy of sirolimus, an inhibitor of T cell growth factors signal, with mycophenolate mofetil, an agent that blocks purine biosynthesis in lymphocytes. Data show that this drug association produces synergistic effects in prolongation of allograft survival in a model of cardiac, pancreatic, and renal transplantation in the rat. This immunosuppressive protocol is promising since no calcineurin inhibitors are needed. Thus, their long-term toxicities are avoided.; The second manuscript reports the effect of the combined therapy of the malononitrilamide FK778, a new inhibitor of pyrimidine biosynthesis in lymphocytes, with tacrolimus, a calcineurin inhibitor that blocks T cell growth factor production. In vitro results show that this drug association produces synergistic effects in B cells proliferation, but antagonistic effects in T cells, in mice, nonhuman primates and humans. In vivo data report that the combination of FK778 and tacrolimus extends renal allograft survival in the rat, in a synergistic manner. Moreover, the level of synergism seems to be schedule-dependant of drugs administration.; The third study evaluates the drug association of WAY-160279, a novel antagonist of VLA-4 adhesion molecule, with sirolimus. The results demonstrate that this combined therapy can prolong allograft survival in an additive to synergistic way, and reverse acute rejection in the heart transplantation model in rats.; Data from the fourth study, which investigates the combination therapy of rPSGL-Ig, a new inhibitor of P-selectin adhesion molecule, with a conventional immunosuppressant, suggest that rPSGL-Ig prolongs significantly rat renal allograft survival when combined with cyclosporine but not with sirolimus, tacrolimus or mycophenolate mofetil.; In conclusion, we investigated in vitro and in vivo effects of four combination therapies of immunosuppressants, including three new molecules (FK778, WAY-160279, and rPSGL-Ig), in prevention of acute rejection of vascularized allografts in the rat. The overall results in rodents are promising and would warrant preclinical evaluation of these drug combinations in nonhuman primates. |
