BLT1-mediated T cell trafficking is critical for rejection and obliterative bronchiolitis after lung transplantation

J Exp Med. 2005 Jul 4;202(1):97-110. doi: 10.1084/jem.20042481.

Abstract

Leukotriene B4 is a lipid mediator that recently has been shown to have potent chemotactic activity for effector T lymphocytes mediated through its receptor, BLT1. Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model. In addition, we used BLT1-deficient mice and a BLT1 antagonist in two tracheal transplant models of lung transplantation to demonstrate the importance of BLT1 for the recruitment of T cells into tracheal allografts. We also show that BLT1-mediated CD8+ T cell recruitment plays an important role in the development of airway fibroproliferation and obliteration. Finally, in human studies of lung transplant recipients, we found that BLT1 is up-regulated on T lymphocytes isolated from the airways of patients with obliterative bronchiolitis. These data demonstrate that BLT1 contributes to the development of lung rejection and obliterative bronchiolitis by mediating effector T lymphocyte trafficking into the lung. This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Bronchiolitis Obliterans / etiology*
  • Bronchiolitis Obliterans / immunology
  • Bronchiolitis Obliterans / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / physiology*
  • Collagen / metabolism
  • Disease Models, Animal
  • Graft Rejection / etiology*
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Humans
  • Lung Transplantation / adverse effects*
  • Lung Transplantation / immunology
  • Lung Transplantation / pathology
  • Lung Transplantation / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Ovalbumin / immunology
  • Receptors, Leukotriene B4 / deficiency
  • Receptors, Leukotriene B4 / genetics
  • Receptors, Leukotriene B4 / physiology*
  • Trachea / transplantation

Substances

  • Receptors, Leukotriene B4
  • Ovalbumin
  • Collagen