IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

J Clin Invest. 2007 Nov;117(11):3498-506. doi: 10.1172/JCI28031.

Abstract

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, CD / immunology
  • Bronchiolitis Obliterans / immunology*
  • Collagen Type II / immunology
  • Collagen Type V / immunology*
  • Disease Susceptibility*
  • Graft Rejection / immunology*
  • Humans
  • Immunity, Cellular*
  • Interferon-gamma / immunology
  • Interleukin-17 / immunology*
  • Interleukin-1beta / immunology
  • Lung Transplantation* / immunology
  • Lung Transplantation* / pathology
  • Prospective Studies
  • Risk Factors
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Helper-Inducer / immunology
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antigens, CD
  • Collagen Type II
  • Collagen Type V
  • Interleukin-17
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma