title: Adenosine A₂A receptor agonist-mediated increase in donor-derived regulatory T cells suppresses development of graft-versus-host disease.
abstract: Graft-versus-host disease (GVHD) remains a significant complication of allogeneic transplantation. We previously reported that the adenosine A(2A) receptor (A(2A)R) specific agonist, ATL146e, decreases the incidence and severity of GVHD in a mouse transplant model. There is increasing interest in treatments that increase CD4(+)CD25(high)Foxp3(+) regulatory T cells (Tregs) to suppress GVHD. Our current study found in vitro that A(2A)R selective agonists enhanced TGF-β-induced generation of mouse Tregs 2.3- to 3-fold. We demonstrated in vivo suppression of GVHD with specific A(2A)R agonists in two different murine GVHD transplant models associated with profound increases in both circulating and target tissue Tregs of donor origin. Three different A(2A)R agonists of differing potency, ATL146e, ATL370, and ATL1223, all significantly inhibited GVHD-associated weight loss and mortality. At the same time, Tregs shown to be of donor origin increased 5.1- to 7.4-fold in spleen, 2.7- to 4.6-fold in peripheral blood, 2.3- to 4.7-fold in colon, and 3.8- to 4.6-fold in skin. We conclude that specific activation of A(2A)R inhibits acute GVHD through an increase of donor-derived Tregs. Furthermore, the increased presence of Tregs in target tissues (colon and skin) of A(2A)R-specific agonist-treated mice is likely the mechanistic basis for the anti-inflammatory effect preventing acute GVHD.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyu Lee
authors.initials: KL
authors.lastname: Han
authors.forename: Stephenie V M
authors.initials: SV
authors.lastname: Thomas
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Koontz
authors.forename: Cattlena M
authors.initials: CM
authors.lastname: Changpriroa
authors.forename: Seung-Kwon
authors.initials: SK
authors.lastname: Ha
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kang
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D007108:Immune Tolerance / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D016212:Transforming Growth Factor beta