Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection

Andrea Vergani, Carmen Fotino, Francesca D'Addio, Sara Tezza, Michele Podetta, Francesca Gatti, Melissa Chin, Roberto Bassi, Ruth D. Molano, Domenico Corradi, Rita Gatti, Maria E. Ferrero, Antonio Secchi, Fabio Grassi, Camillo Ricordi, Mohamed H. Sayegh, Paola Maffi, Antonello Pileggi, Paolo Fiorina

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62 Scopus citations

Abstract

The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damageactivation, 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-in fi ltrating 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 periodateoxidized 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.

Original languageEnglish (US)
Pages (from-to)1665-1675
Number of pages11
JournalDiabetes
Volume62
Issue number5
DOIs
StatePublished - May 1 2013

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Vergani, A., Fotino, C., D'Addio, F., Tezza, S., Podetta, M., Gatti, F., Chin, M., Bassi, R., Molano, R. D., Corradi, D., Gatti, R., Ferrero, M. E., Secchi, A., Grassi, F., Ricordi, C., Sayegh, M. H., Maffi, P., Pileggi, A., & Fiorina, P. (2013). Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes, 62(5), 1665-1675. https://doi.org/10.2337/db12-0242