title: Mechanism analysis of long-term graft survival by monocarboxylate transporter-1 inhibition.
abstract: BACKGROUND
  Monocarboxylate transporter (MCT)-1, a member of a family of molecules, transports monocarboxylates such as lactate. Inhibiting MCT-1 leads to long-term graft survival in rodent heart transplantation and induces tolerance. We evaluated an MCT-1 inhibitor, AS2495674, in a rat heart transplant model and analyzed its underlying mechanism.
  
  
  METHODS
  AS2495674 was tested on rat lymphocytes to determine its effect on lactate accumulation, proliferation, and immunoglobulin production. The effect of AS2495674 on graft survival was tested on the Brown Norway to Lewis rat strain combination with a second heart transplantation to test donor-specific suppression. Histology and ex vivo analyses were done to examine the AS2495674 effects on the immune response.
  
  
  RESULTS
  In vitro, AS2495674 resulted in lactate accumulation, inhibited lymphocyte proliferation, and prevented immunoglobulin production. AS2495674 induced long-term allograft survival with little evidence of chronic rejection and induced donor-specific suppression. Evaluation of the allograft and peripheral T lymphocytes from the AS2495674 group compared with that of vehicle showed (1) decreased donor-specific T lymphocyte response, (2) more forkhead box P3+ (Foxp3+) and CD45RA+ cells in the allograft, (3) higher gene expression of chemokines and chemokine receptors in the allograft, and (4) preferential inhibition of Foxp3(-) cells with little or no effect on Foxp3+ cells.
  
  
  CONCLUSIONS
  AS2495674 prevents acute rejection, reduces features of chronic rejection, and induces tolerance. Our data suggest that the mechanism of AS2495674 involves generating a tolerogenic graft environment by preferentially targeting T effector cells while sparing the generation of T regulatory cells.
authors.affiliation: Astellas Research Institute of America LLC, Transplantation Immunology, Skokie, IL, USA. Kathy.cho@us.astellas.com
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Cho
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamada
authors.forename: Carmen
authors.initials: C
authors.lastname: Wynn
authors.forename: Heather A
authors.initials: HA
authors.lastname: Behanna
authors.forename: In Chul
authors.initials: IC
authors.lastname: Hong
authors.forename: Vlasios
authors.initials: V
authors.lastname: Manaves
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Abe
authors.forename: Hongsi
authors.initials: H
authors.lastname: Jiang
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Saita
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007136:Immunoglobulins / Q000096:biosynthesis; D007371:Interferon-gamma / Q000378:metabolism; D007773:Lactates / Q000097:blood; D008213:Lymphocyte Activation; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D027981:Symporters / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D007136:Immunoglobulins; D007371:Interferon-gamma; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1