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

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Author
Vergani, Andrea
Fotino, Carmen
D’Addio, Francesca
Tezza, Sara
Podetta, Michele
Gatti, Francesca
Chin, Melissa
Molano, Ruth D.
Corradi, Domenico
Gatti, Rita
Ferrero, Maria E.
Secchi, Antonio
Grassi, Fabio
Ricordi, Camillo
Maffi, Paola
Pileggi, Antonello
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.2337/db12-0242Metadata
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Vergani, A., C. Fotino, F. D’Addio, S. Tezza, M. Podetta, F. Gatti, M. Chin, et al. 2013. “Effect of the Purinergic Inhibitor Oxidized ATP in a Model of Islet Allograft Rejection.” Diabetes 62 (5): 1665-1675. doi:10.2337/db12-0242. http://dx.doi.org/10.2337/db12-0242.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636636/pdf/Terms of Use
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