Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma.
Bronchial asthma is characterized by massive infiltration of eosinophils and airway hyperreactivity (AHR), which are caused by overproduction of Th2 cytokines (IL-4, IL-5, and IL-13) by allergen-specific T cells. We recently demonstrated a critical contribution of OX40 ligand (OX40L) to the development of Th2-mediated experimental leishmaniasis. In this study, we have examined the role of OX40L in the development of Th2-mediated pulmonary inflammation by utilizing OX40L-deficient mice and a neutralizing anti-OX40L mAb in a murine model of asthma. Sensitization and airway challenge with ovalbumin in wild-type BALB/c mice induced a typical allergic asthma characterized by AHR, accumulation of eosinophils, increased mucus production, and high levels of Th2 cytokines in the lung. All these asthmatic responses were not induced in OX40L-deficient BALB/c mice. Administration of neutralizing anti-OX40L mAb in wild-type BALB/c mice during the sensitization period also abolished the induction of asthmatic responses. In contrast, administration of anti-OX40L mAb during the challenge period did not inhibit the asthmatic responses. These results indicate a critical role for OX40L in the induction phase, which leads to the development of pathogenic Th2 cells, but not in the effector phase, which includes migration and activation of pathogenic Th2 cells in the lung.
Hoshino
Akihiko
A
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. a.hoshino@po.rd.taisho.co.jp
Tanaka
Yoshitaka
Y
Akiba
Hisaya
H
Asakura
Yumiko
Y
Mita
Yasuo
Y
Sakurai
Takanobu
T
Takaoka
Akiko
A
Nakaike
Shiro
S
Ishii
Naoto
N
Sugamura
Kazuo
K
Yagita
Hideo
H
Okumura
Ko
K
D000818:Animals; D000911:Antibodies, Monoclonal; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D008168:Lung / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053278:OX40 Ligand; D018418:Th2 Cells / Q000276:immunology*; D048069:Tumor Necrosis Factors
D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors