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* Department of Medicine,
Department of Microbiology,
Cardiovascular Research Center, and
Carter Immunology Center University of Virginia, Charlottesville, VA 22908
The current studies investigated the in vitro and in vivo effect of adenosine 2A receptor (A2AR) agonists to attenuate allogenic immune activation. We performed MLRs with spleen T lymphocytes and APCs isolated from wild-type and A2AR knockout mice of both C57BL/6 and BALB/c background strains. Two-way MLR-stimulated T cell proliferation was reduced by ATL313, a selective A2AR agonist in a dose-responsive manner (
70%; 10 nM), an effect reversed by the A2AR antagonist ZM241385 (100 nM). By one-way MLRs, we observed that ATL313’s inhibitory effect was due to effects on both T cells and APCs. ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-
, RANTES, IL-12P70, and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. In skin transplants, allograft survival was enhanced with ATL313, an effect blocked by ZM241385. These results indicate that A2AR agonists attenuate allogenic recognition by action on both T lymphocytes and APCs in vitro and delayed acute rejection in vivo. We conclude that A2AR agonists may represent a new class of compounds for induction therapy in organ transplantation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants DK56223, DK62324, DK58413, and HL37942.
2 C.P.S. and L.L. participated equally in this study.
3 Address correspondence and reprint requests to Dr. Mark D. Okusa, Division of Nephrology, Box 800133, University of Virginia Health System, Charlottesville, VA 22908. E-mail address: mdo7y{at}virginia.edu
4 Abbreviations used in this paper: IRI, ischemia-reperfusion injury; A2AR, adenosine 2A receptor; DC, dendritic cell; KO, knockout; MCF, mean channel fluorescence; PD, programmed death; PKA, protein kinase A; WT, wild type.
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