The specific monocarboxylate transporter (MCT1) inhibitor, AR-C117977, a novel immunosuppressant, prolongs allograft survival in the mouse.

ABSTRACT

Novel small molecular weight compounds that act by inhibiting the monocarboxylate transporter (MCT1) receptor have been found to cause profound inhibition of T-cell responses to alloantigen in vitro. Here, we have investigated the ability of one compound in this series, AR-C117977, a potent MCT1 inhibitor, to prevent the acute and chronic rejection of vascularized and nonvascularized allografts in the mouse. Treatment with AR-C117977 or cyclosporin A (CsA) administered at a dose of 30 mg/kg subcutaneously for 15 days to adult CBA. Ca (H2(k)) mice, commencing either 3 days or 1 day before transplantation, was found to prolong the survival of an allogeneic (C57BL/10 H2(b); NZW H2(z); or BALB/c H2(d)) heart, aorta, or skin allograft significantly compared with treatment with vehicle alone (median survival time [MST] AR-C117977 treated 15; 19 and 18 days [skin] and 73; 66 and 67 days ([heart] vs. vehicle treated 8, 8 and 9 days [skin] and 9, 8, 10 days [heart] for B10, NZW and BALB grafts, respectively). AR-C117977 also inhibited the development of transplant arteriosclerosis in aortic allografts partially, but was unable to inhibit alloantibody production after transplantation. The specific MCT1 inhibitor AR-C117977 has potent immunosuppressive properties in vivo effectively preventing acute but not chronic allograft rejection in the mouse.