Journal
JOURNAL OF IMMUNOLOGY
Volume 178, Issue 7, Pages 4240-4249Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.178.7.4240
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- NHLBI NIH HHS [HL 37942] Funding Source: Medline
- NIDDK NIH HHS [DK 56223, DK 62324, DK 58413] Funding Source: Medline
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The current studies investigated the in vitro and in vivo effect of adenosine 2A receptor (A(2A)R) agonists to attenuate allogenic immune activation. We performed MLRs with spleen T lymphocytes and APCs isolated from wild-type and A(2A)R 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 (similar to 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-gamma, RANTES, IL-12P(70), 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 A(2A)R agonists attenuate allogenic recognition by action on both T lymphocytes and APCs in vitro and delayed acute rejection in vivo. We conclude that A(2A)R agonists may represent a new class of compounds for induction therapy in organ transplantation.
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