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

  1. Paolo Fiorina1,2
  1. 1Transplantation Research Center, Nephrology Division, Boston Children’s Hospital and Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
  2. 2Transplant Medicine, San Raffaele Scientific Institute, Milan, Italy
  3. 3Diabetes Research Institute, University of Miami, Miami, Florida
  4. 4Pathology and Laboratory Medicine, University of Parma, Parma, Italy
  5. 5Department of Human Morphology and Biomedical Science, University of Milan, Milan, Italy
  6. 6Vita-Salute San Raffaele University, Milan, Italy
  7. 7Institute for Research in Biomedicine, Bellinzona, Switzerland.
  1. Corresponding author: Paolo Fiorina, paolo.fiorina{at}childrens.harvard.edu.

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.

  • Received February 26, 2012.
  • Accepted December 4, 2012.

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  1. Diabetes vol. 62 no. 5 1665-1675
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