Effect of the Purinergic Inhibitor Oxidized-ATP in a Model of Islet Allograft Rejection
- Andrea Vergani1,2,
- Carmen Fotino3,
- Francesca D’Addio2,
- Sara Tezza1,
- Michele Podetta3,
- Francesca Gatti1,
- Melissa Chin1,
- Roberto Bassi1,
- Ruth D. Molano3,
- Domenico Corradi4,
- Rita Gatti4,
- Maria E. Ferrero5,
- Antonio Secchi2,6,
- Fabio Grassi7,
- Camillo Ricordi3,
- Mohamed H. Sayegh1,
- Paola Maffi2,
- Antonello Pileggi3 and
- Paolo Fiorina1,2⇓
- 1Transplantation Research Center, Nephrology Division, Boston Children’s Hospital and Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
- 2Transplant Medicine, San Raffaele Scientific Institute, Milan, Italy
- 3Diabetes Research Institute, University of Miami, Miami, Florida
- 4Pathology and Laboratory Medicine, University of Parma, Parma, Italy
- 5Department of Human Morphology and Biomedical Science, University of Milan, Milan, Italy
- 6Vita-Salute San Raffaele University, Milan, Italy
- 7Institute for Research in Biomedicine, Bellinzona, Switzerland.
- Corresponding author: Paolo Fiorina, .
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.
- Received February 26, 2012.
- Accepted December 4, 2012.
- © 2013 by the American Diabetes Association.
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