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.

journal_name

Transplantation

journal_title

Transplantation

authors

Cho KS,Yamada T,Wynn C,Behanna HA,Hong IC,Manaves V,Nakanishi T,Hirose J,Abe Y,Jiang H,Tamura K,Saita Y

doi

10.1097/TP.0b013e3181ff8818

subject

Has Abstract

pub_date

2010-12-27 00:00:00

pages

1299-306

issue

12

eissn

0041-1337

issn

1534-6080

journal_volume

90

pub_type

杂志文章
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    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1097/01.tp.0000290678.06523.95

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    doi:

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    pub_type: 杂志文章

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    pub_type: 杂志文章

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