title: Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition.
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.
authors: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors: Charles P
authors: CP
authors: Sevigny
authors: Li
authors: L
authors: Li
authors: Alaa S
authors: AS
authors: Awad
authors: Liping
authors: L
authors: Huang
authors: Marcia
authors: M
authors: McDuffie
authors: Joel
authors: J
authors: Linden
authors: Peter I
authors: PI
authors: Lobo
authors: Mark D
authors: MD
authors: Okusa
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D023201:CD40 Ligand / Q000032:analysis / Q000037:antagonists & inhibitors; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000037:antagonists & inhibitors; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor; D043705:Receptor, Adenosine A2A / Q000235:genetics; D015427:Reperfusion Injury / Q000517:prevention & control; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C485468:Cd3e protein, mouse; C556707:Ctla4 protein, mouse; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; C491383:Pdcd1 protein, mouse; D010880:Piperidines; D061026:Programmed Cell Death 1 Receptor; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D023201:CD40 Ligand; D007371:Interferon-gamma; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse