Inhibition of the purinergic pathway prolongs mouse lung allograft survival

Kaifeng Liu, Andrea Vergani, Picheng Zhao, Moufida Ben Nasr, Xiao Wu, Khadija Iken, Dawei Jiang, Xiaofeng Su, Carmen Fotino, Paolo Fiorina, Gary A. Visner

Research output: Contribution to journalArticle

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 alloimmune 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-g 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.

Original languageEnglish
Pages (from-to)300-310
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume51
Issue number2
DOIs
Publication statusPublished - 2014

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Keywords

  • CD8
  • Oxidized ATP
  • P2XR7
  • Transplant

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Liu, K., Vergani, A., Zhao, P., Ben Nasr, M., Wu, X., Iken, K., Jiang, D., Su, X., Fotino, C., Fiorina, P., & Visner, G. A. (2014). Inhibition of the purinergic pathway prolongs mouse lung allograft survival. American Journal of Respiratory Cell and Molecular Biology, 51(2), 300-310. https://doi.org/10.1165/rcmb.2013-0362OC