The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat.
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.
Ekberg
Henrik
H
Department of Nephrology and Transplantation, Lund University, University Hospital, Malmo, Sweden. henrik.ekberg@med.lu.se
Qi
Zhongquan
Z
Pahlman
Clara
C
Veress
Béla
B
Bundick
Robert V
RV
Craggs
Robert I
RI
Holness
Elain
E
Edwards
Susan
S
Murray
Clare M
CM
Ferguson
Douglas
D
Kerry
Philip J
PJ
Wilson
Elaine
E
Donald
David K
DK
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
D006571:Heterocyclic Compounds; D007166:Immunosuppressive Agents; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C525748:AR C117977