title: The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat.
abstract: BACKGROUND
  In a search for immunosuppressive drugs having novel mechanisms, monocarboxylate transporter (MCT-1) inhibitors were identified that markedly inhibited immune responses. Here, we report the effects of AR-C117977, a potent MCT-1 inhibitor, on alloimmune responses in the rat.
  
  
  METHODS
  In vitro activity was determined in a rat mixed lymphocyte response (MLR). In vivo activity was tested in a graft versus host response (GVHR) and in both high (DA to PVG) and low (PVG to DA) responder cardiac allograft models. To assess induction of donor-specific suppression recipients of allogeneic hearts surviving longer than 100 days received a second transplant either of the same donor strain or a third-party donor strain. Effects on chronic graft rejection were assessed histologically by evaluating vasculopathy in long-term surviving grafts and in an obliterative bronchiolitis (OB) model.
  
  
  RESULTS
  AR-C117977 inhibited the rat MLR and was more potent than cyclosporin A (CsA). In the rat GVHR model, AR-C117977 gave a dose-related inhibition. In the high responder cardiac allograft model, graft survival in excess of 100 days was achieved with AR-C117977 compared with 20 days with CsA and all the long-term survivors exhibited donor-specific suppression on retransplantation. In the low responder model, both AR-C117977 and CsA induced survival in excess of 100 days. Histology of the long-term surviving grafts suggested reduced vasculopathy associated with chronic rejection. Furthermore, AR-C117977 inhibited the occlusion of transplanted trachea in a OB model.
  
  
  CONCLUSIONS
  This report describes a MCT-1 specific inhibitor having immunosuppressive activity on alloimmune responses and inducing donor-specific suppression.
authors.affiliation: Department of Nephrology and Transplantation, Lund University, University Hospital, Malmo, Sweden. henrik.ekberg@med.lu.se
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
authors.forename: Clara
authors.initials: C
authors.lastname: Pahlman
authors.forename: Béla
authors.initials: B
authors.lastname: Veress
authors.forename: Robert V
authors.initials: RV
authors.lastname: Bundick
authors.forename: Robert I
authors.initials: RI
authors.lastname: Craggs
authors.forename: Elain
authors.initials: E
authors.lastname: Holness
authors.forename: Susan
authors.initials: S
authors.lastname: Edwards
authors.forename: Clare M
authors.initials: CM
authors.lastname: Murray
authors.forename: Douglas
authors.initials: D
authors.lastname: Ferguson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kerry
authors.forename: Elaine
authors.initials: E
authors.lastname: Wilson
authors.forename: David K
authors.initials: DK
authors.lastname: Donald
mesh_terms: D000208:Acute Disease; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology; D002908:Chronic Disease; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007959:Lymphocyte Culture Test, Mixed; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors*; D011183:Postoperative Complications / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D027981:Symporters / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D006571:Heterocyclic Compounds; D007166:Immunosuppressive Agents; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C525748:AR C117977