Malononitrilamides synergistically prevent acute and treat ongoing skin allograft rejection with cyclosporine.

The low molecular weight malononitrilamides (MNAs), a new class of immunosuppressive agents, belong to the derivatives of leflunomide's active metabolite, A771726. They have been shown to bind specifically to dehydroorotate dehydrogenase and inhibit de novo pyrimidine biosynthesis, thereby blocking T- and B-cell proliferation and strongly suppressing IgM and IgG antibody production. Here we evaluated their efficacy together with cyclosporine (CyA) in rat skin allotransplantation models, using different strain combinations. Monotherapy of transplanted animals in these models with the MNAs HMR 1279 and HMR 1715 resulted in a significant and dose-dependent prolongation of the graft survival time. Even a short-term application showed efficacy in the prevention of acute rejection. The MNAs were also effective when treatment was started at the time of expected rejection crisis, demonstrating strong therapeutic activity to reverse ongoing acute rejection, whereas CyA was ineffective for the treatment of ongoing allograft rejection episodes. Combination therapy of MNAs with CyA proved to be very effective for the prevention of acute skin graft rejection. Interestingly, whereas CyA alone was unable to treat ongoing acute rejection episodes, comedication of MNAs and CyA, even after a short-term application, was synergistically effective and significantly suppressed ongoing allogeneic skin graft rejection. These results demonstrate that MNAs are potent and well tolerated immunosuppressants with a potential comparable to that of CyA, but they are superior to CyA in their ability to reverse acute rejection episodes. They represent powerful rescue drugs and demonstrate synergistic activity with CyA to prevent acute and treat ongoing skin allograft rejection.