Role of complement activation in obliterative bronchiolitis post-lung transplantation

Hidemi Suzuki, Mark E. Lasbury, Lin Fan, Ragini Vittal, Elizabeth A. Mickler, Heather L. Benson, Rebecca Shilling, Qiang Wu, Daniel J. Weber, Sarah R. Wagner, Melissa Lasaro, Denise Devore, Yi Wang, George E. Sandusky, Kelsey Lipking, Pankita Pandya, John Reynolds, Robert Love, Thomas Wozniak, Hongmei GuKrista M. Brown, David S. Wilkes

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Obliterative bronchiolitis (OB) post-lung transplantation involves IL-17-regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB is unknown. The current study examines the role of complement activation in OB. Complement-regulatory protein (CRP) (CD55, CD46, complement receptor 1-related protein y/CD46) expression was downregulated in human and murine OB; and C3a, a marker of complement activation, was upregulated locally. IL-17 differentially suppressed complement receptor 1-related protein y expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen- or autoantigen (type V collagen)-reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17-mediated downregulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed-forward loop that may enhance CRP downregulation, suggesting that complement blockade could be a therapeutic strategy for OB.

Original languageEnglish (US)
Pages (from-to)4431-4439
Number of pages9
JournalJournal of Immunology
Volume191
Issue number8
DOIs
StatePublished - Oct 15 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Role of complement activation in obliterative bronchiolitis post-lung transplantation'. Together they form a unique fingerprint.

Cite this