Abstract
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 A(2A)R agonist in a dose-responsive manner (approximately 70%; 10 nM), an effect reversed by the A(2A)R 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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine A2 Receptor Agonists*
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Adenosine A2 Receptor Antagonists
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Animals
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Antibodies, Monoclonal / pharmacology
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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation / metabolism
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CD3 Complex / metabolism
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CD40 Ligand / analysis
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CD40 Ligand / antagonists & inhibitors
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CTLA-4 Antigen
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Cytokines / antagonists & inhibitors
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Cytokines / metabolism
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Graft Rejection / pathology
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Graft Rejection / prevention & control*
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism
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Interleukin-2 Receptor alpha Subunit / analysis
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Interleukin-2 Receptor alpha Subunit / antagonists & inhibitors
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Isoantigens / immunology*
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Lymphocyte Activation / drug effects
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Mice
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Mice, Knockout
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Piperidines / pharmacology*
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Piperidines / therapeutic use
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Programmed Cell Death 1 Receptor
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Receptor, Adenosine A2A / genetics
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Reperfusion Injury / prevention & control
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Skin Transplantation / immunology
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Skin Transplantation / pathology
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T-Lymphocytes / chemistry
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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Triazines / pharmacology
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Triazoles / pharmacology
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ZAP-70 Protein-Tyrosine Kinase / metabolism
Substances
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ATL 313
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Adenosine A2 Receptor Agonists
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Adenosine A2 Receptor Antagonists
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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CD3 Complex
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CTLA-4 Antigen
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Cd3e protein, mouse
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Ctla4 protein, mouse
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Cytokines
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Interleukin-2 Receptor alpha Subunit
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Isoantigens
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Pdcd1 protein, mouse
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Piperidines
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Programmed Cell Death 1 Receptor
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Receptor, Adenosine A2A
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Triazines
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Triazoles
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ZM 241385
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CD40 Ligand
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Interferon-gamma
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse