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

Transplantation. 2007 Nov 15;84(9):1204-7. doi: 10.1097/01.tp.0000287543.91765.41.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / transplantation*
  • Graft Survival / drug effects
  • Graft Survival / immunology*
  • Heart Transplantation / immunology*
  • Heterocyclic Compounds / therapeutic use*
  • Immunosuppressive Agents / therapeutic use*
  • Isoantibodies / blood*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Monocarboxylic Acid Transporters / antagonists & inhibitors*
  • Symporters / antagonists & inhibitors*
  • Transplantation, Homologous / immunology*

Substances

  • AR C117977
  • Heterocyclic Compounds
  • Immunosuppressive Agents
  • Isoantibodies
  • Monocarboxylic Acid Transporters
  • Symporters
  • monocarboxylate transport protein 1