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 language | English |
|---|---|
| Pages (from-to) | 463-475 |
| Number of pages | 13 |
| Journal | Circulation |
| Volume | 127 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jan 29 2013 |
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Keywords
- Immunology
- P2X7R
- Rejection
- Transplantation
ASJC Scopus subject areas
- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Cite this
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 journal › Article
}
TY - JOUR
T1 - Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7
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
PY - 2013/1/29
Y1 - 2013/1/29
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.
KW - Immunology
KW - P2X7R
KW - Rejection
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=84873145622&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873145622&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.112.123653
DO - 10.1161/CIRCULATIONAHA.112.123653
M3 - Article
C2 - 23250993
AN - SCOPUS:84873145622
VL - 127
SP - 463
EP - 475
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 4
ER -