The Journal of Experimental Medicine
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Published 5 July 2005. doi:10.1084/jem.20042481
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 1, 97-110
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ARTICLE

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

Benjamin D. Medoff1,2, Edward Seung1, John C. Wain1,3, Terry K. Means1, Gabriele S.V. Campanella1, Sabina A. Islam1, Seddon Y. Thomas1, Leo C. Ginns2, Nir Grabie4, Andrew H. Lichtman4, Andrew M. Tager1,2, and Andrew D. Luster1

1 Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
2 Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
3 Division of Thoracic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
4 Immunology Research Division and Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Andrew D. Luster: luster.andrew{at}mgh.harvard.edu

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.

Abbreviations used: AR, acute rejection; BAL, bronchoalveolar lavage; CC10, Clara cell secretory protein; LTB4, leukotriene B4; OB, obliterative bronchiolitis; QPCR, quantitative PCR; Penh, enhanced pause.

B.D. Medoff and E. Seung contributed equally to this work.


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