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Effect of the Purinergic Inhibitor Oxidized ATP in a Model of Islet Allograft Rejection

Authors :
Paola Maffi
Antonello Pileggi
Domenico Corradi
Sara Tezza
R. D. Molano
Francesca D'Addio
Francesca Gatti
Paolo Fiorina
Melissa Chin
Mohamed H. Sayegh
Carmen Fotino
Antonio Secchi
Fabio Grassi
Maria Elena Ferrero
Rita Gatti
Andrea Vergani
Camillo Ricordi
Michele Podetta
Roberto Bassi
Andrea, Vergani
Carmen, Fotino
Francesca, D’Addio
Sara, Tezza
Michele, Podetta
Francesca, Gatti
Melisa, Chin
Roberto, Bassi
Molano, Ruth D.
Domenico, Corradi
Rita, Gatti
Ferrero, Maria E.
Secchi, Antonio
Fabio, Grassi
Camillo, Ricordi
Sayegh, Mohamed H.
Maffi, PAOLA ANGELA MARIA
Antonello, Pileggi
Paolo, Fiorina
Source :
Diabetes
Publication Year :
2013
Publisher :
American Diabetes Association, 2013.

Abstract

The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function.

Details

Language :
English
ISSN :
1939327X and 00121797
Volume :
62
Issue :
5
Database :
OpenAIRE
Journal :
Diabetes
Accession number :
edsair.doi.dedup.....a5e576e568193c7f58b5423e3bf68496