Impairment of bleomycin-induced lung fibrosis in CD28-deficient mice.
Lung fibrosis is an important pulmonary disease with a high mortality rate, but its pathophysiological mechanism has not been fully clarified. Various types of cells have been implicated in the development of lung fibrosis, including T cells. However, the contribution of functional molecules expressed on T cells to the development of lung fibrosis remains largely unknown. In this study, we determined whether costimulation via CD28 on T cells was crucial for the development of lung fibrosis by intratracheally administering bleomycin into CD28-deficient mice. Compared with wild-type mice, the CD28-deficient mice showed markedly impaired lung fibrosis after injection with low doses of bleomycin, as judged by histological changes and hydroxyproline content in the lungs. In addition, bleomycin-induced T cell infiltration into the airways and production of several cytokines and chemokines including IL-5 were also impaired in the CD28-deficient mice. Furthermore, adoptive transfer of CD28-positive T cells from wild-type mice recovered the impaired bleomycin-induced lung fibrosis in CD28-deficient mice. These findings suggest that the CD28-mediated T cell costimulation plays a critical role in the development of lung fibrosis, possibly by regulating the production of cytokines and chemokines in the lung. Thus, manipulation of the CD28-mediated costimulation could be a potential therapeutic strategy for the prevention of lung fibrosis.
Okazaki
T
T
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Nakao
A
A
Nakano
H
H
Takahashi
F
F
Takahashi
K
K
Shimozato
O
O
Takeda
K
K
Yagita
H
H
Okumura
K
K
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen; D001761:Bleomycin / Q000008:administration & dosage*; D018106:CD28 Antigens / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D007442:Intubation, Intratracheal; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000637:transplantation
D015703:Antigens, CD; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D018925:Chemokines; D016207:Cytokines; D008562:Membrane Glycoproteins; D001761:Bleomycin