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.

Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection / A. Vergani, C. Fotino, F. D'Addio, S. Tezza, M. Podetta, F. Gatti, M. Chin, R. Bassi, R.D. Molano, D. Corradi, R. Gatti, M.E. Ferrero, A. Secchi, F. Grassi, C. Ricordi, M.H. Sayegh, P. Maffi, A. Pileggi, P. Fiorina. - In: DIABETES. - ISSN 0012-1797. - 62:5(2013), pp. 1665-1675. [10.2337/db12-0242]

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

F. D'Addio;M.E. Ferrero;F. Grassi;P. Fiorina
2013

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. © 2013 by the American Diabetes Association.
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 MED/04 - Patologia Generale
Article (author)
File in questo prodotto:
File Dimensione Formato  
1665.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 3.08 MB
Formato Adobe PDF
3.08 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/236655
Citazioni
  • ???jsp.display-item.citation.pmc??? 37
  • Scopus 68
  • ???jsp.display-item.citation.isi??? 69
social impact