Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7

Andrea Vergani, Sara Tezza, Francesca D'Addio, Carmen Fotino, Kaifeng Liu, Monika Niewczas, Roberto Bassi, Ruth Molano, Sonja Kleffel, Alessandra Petrelli, Antonio Soleti, Enrico Ammirati, Maria Frigerio, Gary Visner, Fabio Grassi, Maria E. Ferrero, Domenico Corradi, Reza Abdi, Camillo Ricordi, Mohamed H. SayeghAntonello Pileggi, Paolo Fiorina

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Background: Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine ATP, released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T-cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation. Methods and Results: We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T-cell activation, T-helper cell 1/T-helper cell 17 differentiation, and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well. Conclusions: P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.

Original languageEnglish
Pages (from-to)463-475
Number of pages13
JournalCirculation
Volume127
Issue number4
DOIs
StatePublished - Jan 29 2013

Fingerprint

Purinergic P2X7 Receptors
Transplants
Heart Transplantation
Th1 Cells
T-Lymphocytes
Allografts
Lymphocytes
Th17 Cells
Immunosuppressive Agents
Cell Differentiation
Up-Regulation
Heart Failure
Adenosine Triphosphate
Phosphorylation
Infection
Neoplasms

Keywords

  • Immunology
  • P2X7R
  • Rejection
  • Transplantation

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Vergani, A., Tezza, S., D'Addio, F., Fotino, C., Liu, K., Niewczas, M., ... Fiorina, P. (2013). Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation, 127(4), 463-475. https://doi.org/10.1161/CIRCULATIONAHA.112.123653

Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. / Vergani, Andrea; Tezza, Sara; D'Addio, Francesca; Fotino, Carmen; Liu, Kaifeng; Niewczas, Monika; Bassi, Roberto; Molano, Ruth; Kleffel, Sonja; Petrelli, Alessandra; Soleti, Antonio; Ammirati, Enrico; Frigerio, Maria; Visner, Gary; Grassi, Fabio; Ferrero, Maria E.; Corradi, Domenico; Abdi, Reza; Ricordi, Camillo; Sayegh, Mohamed H.; Pileggi, Antonello; Fiorina, Paolo.

In: Circulation, Vol. 127, No. 4, 29.01.2013, p. 463-475.

Research output: Contribution to journalArticle

Vergani, A, Tezza, S, D'Addio, F, Fotino, C, Liu, K, Niewczas, M, Bassi, R, Molano, R, Kleffel, S, Petrelli, A, Soleti, A, Ammirati, E, Frigerio, M, Visner, G, Grassi, F, Ferrero, ME, Corradi, D, Abdi, R, Ricordi, C, Sayegh, MH, Pileggi, A & Fiorina, P 2013, 'Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7', Circulation, vol. 127, no. 4, pp. 463-475. https://doi.org/10.1161/CIRCULATIONAHA.112.123653
Vergani, Andrea ; Tezza, Sara ; D'Addio, Francesca ; Fotino, Carmen ; Liu, Kaifeng ; Niewczas, Monika ; Bassi, Roberto ; Molano, Ruth ; Kleffel, Sonja ; Petrelli, Alessandra ; Soleti, Antonio ; Ammirati, Enrico ; Frigerio, Maria ; Visner, Gary ; Grassi, Fabio ; Ferrero, Maria E. ; Corradi, Domenico ; Abdi, Reza ; Ricordi, Camillo ; Sayegh, Mohamed H. ; Pileggi, Antonello ; Fiorina, Paolo. / Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. In: Circulation. 2013 ; Vol. 127, No. 4. pp. 463-475.
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AU - Vergani, Andrea

AU - Tezza, Sara

AU - D'Addio, Francesca

AU - Fotino, Carmen

AU - Liu, Kaifeng

AU - Niewczas, Monika

AU - Bassi, Roberto

AU - Molano, Ruth

AU - Kleffel, Sonja

AU - Petrelli, Alessandra

AU - Soleti, Antonio

AU - Ammirati, Enrico

AU - Frigerio, Maria

AU - Visner, Gary

AU - Grassi, Fabio

AU - Ferrero, Maria E.

AU - Corradi, Domenico

AU - Abdi, Reza

AU - Ricordi, Camillo

AU - Sayegh, Mohamed H.

AU - Pileggi, Antonello

AU - Fiorina, Paolo

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N2 - Background: Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine ATP, released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T-cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation. Methods and Results: We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T-cell activation, T-helper cell 1/T-helper cell 17 differentiation, and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well. Conclusions: P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.

AB - Background: Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine ATP, released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T-cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation. Methods and Results: We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T-cell activation, T-helper cell 1/T-helper cell 17 differentiation, and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well. Conclusions: P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.

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