title: Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection.
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.
authors: Transplantation Research Center, Nephrology Division, Boston Children's Hospital and Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA.
authors: Andrea
authors: A
authors: Vergani
authors: Carmen
authors: C
authors: Fotino
authors: Francesca
authors: F
authors: D'Addio
authors: Sara
authors: S
authors: Tezza
authors: Michele
authors: M
authors: Podetta
authors: Francesca
authors: F
authors: Gatti
authors: Melissa
authors: M
authors: Chin
authors: Roberto
authors: R
authors: Bassi
authors: Ruth D
authors: RD
authors: Molano
authors: Domenico
authors: D
authors: Corradi
authors: Rita
authors: R
authors: Gatti
authors: Maria E
authors: ME
authors: Ferrero
authors: Antonio
authors: A
authors: Secchi
authors: Fabio
authors: F
authors: Grassi
authors: Camillo
authors: C
authors: Ricordi
authors: Mohamed H
authors: MH
authors: Sayegh
authors: Paola
authors: P
authors: Maffi
authors: Antonello
authors: A
authors: Pileggi
authors: Paolo
authors: P
authors: Fiorina
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D058920:Purinergic P2X Receptor Antagonists / Q000627:therapeutic use*; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D016042:Transplantation, Heterotopic / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D007166:Immunosuppressive Agents; C546469:P2rx7 protein, mouse; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C004282:periodate-oxidized adenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D020123:Sirolimus