title: 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, 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.
  
  
  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.
authors.affiliation: Transplantation Research Center, Boston Children's Hospital, Harvard Medical School, Enders Building 5th floor, Rm EN530, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.forename: Carmen
authors.initials: C
authors.lastname: Fotino
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Liu
authors.forename: Monika
authors.initials: M
authors.lastname: Niewczas
authors.forename: Roberto
authors.initials: R
authors.lastname: Bassi
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.forename: Alessandra
authors.initials: A
authors.lastname: Petrelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Soleti
authors.forename: Enrico
authors.initials: E
authors.lastname: Ammirati
authors.forename: Maria
authors.initials: M
authors.lastname: Frigerio
authors.forename: Gary
authors.initials: G
authors.lastname: Visner
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ferrero
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality*; D016027:Heart Transplantation / Q000276:immunology / Q000401:mortality*; D006801:Humans; D007121:Immunocompetence / Q000187:drug effects / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017741:Survivors / Q000706:statistics & numerical data; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D007519:Isoantigens; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C004282:periodate-oxidized adenosine 5'-triphosphate; D000255:Adenosine Triphosphate