Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition.
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.
Sevigny
Charles P
CP
Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Li
Li
L
Awad
Alaa S
AS
Huang
Liping
L
McDuffie
Marcia
M
Linden
Joel
J
Lobo
Peter I
PI
Okusa
Mark D
MD
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
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