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. © 2013 by the American Diabetes Association.
|Titolo:||Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection|
|Parole Chiave:||Immunosuppression ; Adenosine Triphosphate ; Adult ; Animals ; Female ; Graft Rejection ; Humans ; Immunosuppressive Agents ; Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7 ; Sirolimus ; T-Lymphocyte Subsets ; Transplantation, Heterotopic ; Transplantation, Homologous ; Transplantation, Isogeneic|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2013|
|Digital Object Identifier (DOI):||10.2337/db12-0242|
|Appare nelle tipologie:||01 - Articolo su periodico|