Adenosine A2A receptor agonist-mediated increase in donor-derived regulatory T cells suppresses development of graft-versus-host disease.
J Immunol
; 190(1): 458-68, 2013 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-23225892
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-ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Purinas
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Regulação para Baixo
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Regulação para Cima
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Linfócitos T Reguladores
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Ácidos Cicloexanocarboxílicos
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Agonistas do Receptor A2 de Adenosina
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Doença Enxerto-Hospedeiro
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article