Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7

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 as well as with the development of complications including infections and malignancies. The development of a novel, short-term and effective immunomodulatory protocol will thus be an important achievement. The purine adenosine 5′-triphosphate (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 (oATP) 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, Th1/Th17 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 Th1/Th17 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.

Accelerated Tumor Progression in Mice Lacking the ATP Receptor P2X7

“…Lack of the P2X7R prevents GVHD (8) and P2X7R targeting increases long-term survival of heart and pancreatic islets transplants (9,10). Thus, we hypothesized that host P2X7R deletion might facilitate tumor progression.…”

“…6, 7), thus the question arises as to what extent host P2X7R is needed to control tumor growth, and whether P2X7R blockade might impair the antitumor immune response. Previous studies show that genetic deletion of P2X7R prevents GVHD (8), and that P2X7R blockade prevents rejection of allogeneic transplants (9,10).…”

Cardiac purinergic signalling in health and disease

“…There was significant reduction of ATP levels in 1-day-old blood compared to fresh blood, suggesting that fresh blood should be used for assessing T cell immune function in transplant patients [783]. A recent study found that P2X7R are specifically upregulated in graft-infiltrating lymphocytes in cardiactransplanted humans and mice [784]. Furthermore, a shortterm treatment with a P2XR antagonist prolonged cardiac transplant survival [784].…”

“…A recent study found that P2X7R are specifically upregulated in graft-infiltrating lymphocytes in cardiactransplanted humans and mice [784]. Furthermore, a shortterm treatment with a P2XR antagonist prolonged cardiac transplant survival [784].…”

P2X7 receptor in skin biology and diseases

“…Studies in transplantation have shown upregulation of P2X7 expression on infiltrating lymphocytes in transplanted hearts in human patients [106] . Pharmacological blockade and genetic deletion of P2X7 in murine models leads to a delay in allograft rejection, which has been demonstrated in several transplant models including models of islet [107] , heart [106] and lung [108] transplantation. However, with the exception of one preliminary report [109] , there are limited studies investigating P2X7 in skin transplants.…”