Plasma CXCL9 and CXCL10 at allograft injury predict chronic lung allograft dysfunction

Am J Transplant. 2022 Sep;22(9):2169-2179. doi: 10.1111/ajt.17108. Epub 2022 Jun 15.

Abstract

Histopathologic lung allograft injuries are putative harbingers for chronic lung allograft dysfunction (CLAD). However, the mechanisms responsible are not well understood. CXCL9 and CXCL10 are potent chemoattractants of mononuclear cells and potential propagators of allograft injury. We hypothesized that these chemokines would be quantifiable in plasma, and would associate with subsequent CLAD development. In this prospective multicenter study, we evaluated 721 plasma samples for CXCL9/CXCL10 levels from 184 participants at the time of transbronchial biopsies during their first-year post-transplantation. We determined the association between plasma chemokines, histopathologic injury, and CLAD risk using Cox proportional hazards models. We also evaluated CXCL9/CXCL10 levels in bronchoalveolar lavage (BAL) fluid and compared plasma to BAL with respect to CLAD risk. Plasma CXCL9/CXCL10 levels were elevated during the injury patterns associated with CLAD, acute rejection, and acute lung injury, with a dose-response relationship between chemokine levels and CLAD risk. Importantly, there were strong interactions between injury and plasma CXCL9/CXCL10, where histopathologic injury associated with CLAD only in the presence of elevated plasma chemokines. We observed similar associations and interactions with BAL CXCL9/CXCL10 levels. Elevated plasma CXCL9/CXCL10 during allograft injury may contribute to CLAD pathogenesis and has potential as a minimally invasive immune monitoring biomarker.

Keywords: cytokines/cytokine receptors; immunobiology; lung (allograft) function/dysfunction; lung failure/injury; lung transplantation/pulmonology; lung transplantation: living donor; pathology/histopathology; rejection: acute; translational research/science.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Allografts
  • Biomarkers
  • Chemokine CXCL10
  • Chemokine CXCL9
  • Graft Rejection / diagnosis
  • Graft Rejection / etiology
  • Graft vs Host Disease*
  • Humans
  • Lung
  • Lung Transplantation* / adverse effects
  • Prospective Studies

Substances

  • Biomarkers
  • CXCL10 protein, human
  • CXCL9 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL9