title: Inhibition of the purinergic pathway prolongs mouse lung allograft survival.
abstract: Lung transplantation has limited survival with current immunosuppression. ATP is released from activated T cells, which act as costimulatory molecules through binding to the purinergic receptor P2XR7. We investigated the role of blocking the ATP/purinergic pathway, primarily P2XR7, using its inhibitor oxidized ATP (oATP) in modulating rejection of mouse lung allografts. Mouse lung transplants were performed using mice with major histocompatibility complex mismatch, BALB/c to C57BL6. Recipients received suramin or oATP, and lung allografts were evaluated 15 to ≥ 60 days after transplantation. Recipients were also treated with oATP after the onset of moderate to severe rejection to determine its ability to rescue lung allografts. Outcomes measures included lung function, histology, thoracic imaging, and allo-immune responses. Blocking purinergic receptors with the nonselective inhibitor suramin or with the P2XR7-selective inhibitor oATP reduced acute rejection and prolonged lung allograft survival for ≥ 60 days with no progression in severity. There were fewer inflammatory cells within lung allografts, less rejection, and improved lung function, which was maintained over time. CD4 and CD8 T cells were reduced within lung allografts with impaired activation with prolonged impairment of CD8 responses. In vitro, oATP reduced CD8 activation of Th1 inflammatory cytokines IFN-γ and TNF-α and cytolytic machinery, granzyme B. Cotreatment with immunosuppressive agents, cyclosporine, rapamycin, or CTLA-4Ig resulted in no additive benefits, and oATP alone resulted in better outcomes than cyclosporine alone. This study illustrates a potential new pathway to target in hopes of prolonging survival of lung transplant recipients.
authors.affiliation: 1 Department of Medicine/Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Liu
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.forename: Picheng
authors.initials: P
authors.lastname: Zhao
authors.forename: Moufida
authors.initials: M
authors.lastname: Ben Nasr
authors.forename: Xiao
authors.initials: X
authors.lastname: Wu
authors.forename: Khadija
authors.initials: K
authors.lastname: Iken
authors.forename: Dawei
authors.initials: D
authors.lastname: Jiang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Su
authors.forename: Carmen
authors.initials: C
authors.lastname: Fotino
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.forename: Gary A
authors.initials: GA
authors.lastname: Visner
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006648:Histocompatibility; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013498:Suramin / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C017199:2',3'-dialdehyde ATP; D013498:Suramin; D000255:Adenosine Triphosphate
keywords: CD8; P2XR7; oxidized ATP; transplant