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The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat

Ekberg, Henrik LU ; Qi, Zhongquan; Pahlman, Clara; Veress, Bela; Bundick, Robert V.; Craggs, Robert I.; Holness, Elain; Edwards, Susan; Murray, Clare M. and Ferguson, Douglas, et al. (2007) In Transplantation 84(9). p.1191-1199
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... (More)
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 (013) 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 013 model. Conclusion. This report describes a MCT-1 specific inhibitor having immunosuppressive activity on alloinimune responses and inducing donor-specific suppression. (Less)
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Contribution to journal
publication status
published
subject
keywords
donor-specific suppression, alloimmune responses, immunosuppression, monocarboxylate transporter
in
Transplantation
volume
84
issue
9
pages
1191 - 1199
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000251030600019
  • scopus:36249023288
ISSN
1534-6080
DOI
10.1097/01.tp.0000287541.53389.be
language
English
LU publication?
yes
id
e1178237-45a2-4c18-86d8-d6c7c97c583b (old id 968980)
alternative location
http://www.transplantjournal.com/pt/re/transplantation/abstract.00007890-200711150-00019.htm
date added to LUP
2008-01-29 13:15:42
date last changed
2017-06-04 04:23:41
@article{e1178237-45a2-4c18-86d8-d6c7c97c583b,
  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 (013) 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 013 model. Conclusion. This report describes a MCT-1 specific inhibitor having immunosuppressive activity on alloinimune responses and inducing donor-specific suppression.},
  author       = {Ekberg, Henrik and Qi, Zhongquan and Pahlman, Clara and Veress, Bela and Bundick, Robert V. and Craggs, Robert I. and Holness, Elain and Edwards, Susan and Murray, Clare M. and Ferguson, Douglas and Kerry, Philip J. and Wilson, Elaine and Donald, David K.},
  issn         = {1534-6080},
  keyword      = {donor-specific suppression,alloimmune responses,immunosuppression,monocarboxylate transporter},
  language     = {eng},
  number       = {9},
  pages        = {1191--1199},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Transplantation},
  title        = {The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat},
  url          = {http://dx.doi.org/10.1097/01.tp.0000287541.53389.be},
  volume       = {84},
  year         = {2007},
}