Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition

Charles P. Sevigny, Li Li, Alaa S. Awad, Liping Huang, Marcia McDuffie, Joel Linden, Peter I. Lobo, Mark D. Okusa

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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-γ, RANTES, DL-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.

Original languageEnglish (US)
Pages (from-to)4240-4249
Number of pages10
JournalJournal of Immunology
Volume178
Issue number7
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Sevigny, C. P., Li, L., Awad, A. S., Huang, L., McDuffie, M., Linden, J., Lobo, P. I., & Okusa, M. D. (2007). Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. Journal of Immunology, 178(7), 4240-4249. https://doi.org/10.4049/jimmunol.178.7.4240