The effect of Monocarboxylate Transporter (MCT1) inhibitor, AR-C117977 on accelerated rejection of cardiac grafts in pre-sensitised rats and concordant xenotransplantation

Abstract

Previous studies have demonstrated the immunosuppressive properties of the monocarboxylate transporter MCT1 inhibitor, AR-C117977. The objective of this study was to evaluate the possible limitations in immunosuppressive efficacy of AR-C117977 in models of hyper acute rejection of cardiac transplants in pre-sensitised rats and in concordant cardiac xenotransplantation. Methods:A primary graft was given without treatment in order to induce sensitisation. At 10 days, a second cardiac transplant was performed, and doses of the test compound were given and compared to or combined with cyclosporin (CsA). Serum samples were retrieved for flow cytometry and measurements of antibody from the presensitised recipients before and after the second transplantation.Results: Survival was significantly prolonged with AR-C117977 in combination with CsA (median 12.5 days) compared with single treatment. AR-C117977 had a better effect on antibody formation and binding to B-cells than CsA, but a similar effect on T-cells. Acute rejection could not be prevented in any of the treatment groups in the xenotransplant model. Conclusion:A short course of the MCT1 inhibitor AR-C117977, in combination with CsA, prevented accelerated acute rejection in presensitised rats, but no longterm graft survival was achieved. Rejection in xenotransplantation was not prevented.