BLT1-mediated T cell trafficking is critical for rejection and obliterative bronchiolitis after lung transplantation.
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.
Medoff
Benjamin D
BD
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Seung
Edward
E
Wain
John C
JC
Means
Terry K
TK
Campanella
Gabriele S V
GS
Islam
Sabina A
SA
Thomas
Seddon Y
SY
Ginns
Leo C
LC
Grabie
Nir
N
Lichtman
Andrew H
AH
Tager
Andrew M
AM
Luster
Andrew D
AD
D000818:Animals; D001483:Base Sequence; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014132:Trachea / Q000637:transplantation
D018102:Receptors, Leukotriene B4; D010047:Ovalbumin; D003094:Collagen