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Partial Inhibition of Integrin vβ6 Prevents Pulmonary Fibrosis without Exacerbating Inflammation

¹ Departments of Exploratory Biology, Fibrosis, Protein Chemistry, Gene Discovery, Molecular Profiling, and Clinical Sciences and Technology, Biogen Idec, Cambridge, Massachusetts; ² Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ³ Division of Rheumatology, Mayo Clinic, Rochester, Minnesota; ⁴ Section of Rheumatology, Department of Pathology, Boston University School of Medicine, Boston, Massachusetts; ⁵ Pulmonary Disease and Critical Care Medicine Unit, Department of Medicine, University of Vermont, Burlington, Vermont; and ⁶ Lung Biology Center, University of California San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Gerald S. Horan, Ph.D., Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142. E-mail: gerald.horan{at}biogenidec.com

Rationale: Transforming growth factor (TGF)-β has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin vβ6, a key activator of TGF-β in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-β at sites of vβ6 up-regulation without affecting other homeostatic roles of TGF-β.

Objectives: To analyze the expression of vβ6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of vβ6-mediated TGF-β activation in murine bleomycin–induced pulmonary fibrosis.

Methods: Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for vβ6 expression. A range of concentrations of a monoclonal antibody that blocks vβ6-mediated TGF-β activation was evaluated in murine bleomycin–induced lung fibrosis.

Measurements and Main Results: vβ6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, vβ6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-β inhibition in the lung. Low doses of antibody attenuated collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers.

Conclusions: Partial inhibition of TGF-β using vβ6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of vβ6, an activator of the fibrogenic cytokine, TGF-β, in human pulmonary fibrosis suggests that vβ6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.

Key Words: alphavbeta6 • fibrosis • integrin • transforming growth factor-β

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Transforming growth factor (TGF)-β is an important driver of pulmonary fibrosis and therapeutic strategies to inhibit its actions are sought. However, TGF-β has other homeostatic roles that could make therapeutic inhibition problematic. What This Study Adds to the Field Monoclonal antibodies against a tissue-restricted activator of TGF-β, vβ6, can inhibit fibrosis at doses that do not exacerbate inflammation, thus avoiding potential risks associated with global TGF-β inhibition.

 

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Inhibition of Integrin vβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung Fibrosis

Khalid Puthawala, Nicos Hadjiangelis, Steven C. Jacoby, Emmanuel Bayongan, Zhicheng Zhao, Zhiwei Yang, Mary Louise Devitt, Gerald S. Horan, Paul H. Weinreb, Matvey E. Lukashev, Shelia M. Violette, Kristen S. Grant, Cristina Colarossi, Silvia C. Formenti, and John S. Munger
AJRCCM 2008 177: 82-90. [Abstract] [Full Text]  

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