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Published ahead of print on October 24, 2003, doi:10.1164/rccm.200304-543OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 97-104, (2004)
© 2004 American Thoracic Society

A Monoclonal Antibody to {alpha}1ß1 Blocks Antigen-induced Airway Responses in Sheep

William M. Abraham, Ashfaq Ahmed, Irakli Serebriakov, Amie N. Carmillo, Janine Ferrant, Antonin R. de Fougerolles, Ellen A. Garber, Philip J. Gotwals, Victor E. Koteliansky, Fred Taylor and Roy R. Lobb

Division of Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida; and Biogen, Inc., Cambridge, Massachusetts

Correspondence and requests for reprints should be addressed to William M. Abraham, Ph.D., Department of Research, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140. E-mail: abraham{at}msmc.com

The integrin {alpha}1ß1 (very late antigen-1; CD49a/CD29) is a major adhesion receptor for collagen I, IV, and VI, and its induced expression on activated monocytes and lymphocytes plays a central role in their retention and activation at inflammatory sites in autoimmune pathologies. However, the role of {alpha}1ß1 in allergic settings has not been explored. In this study, we show that a single 45-mg dose of aerosolized monoclonal antibody AQC2 to the {alpha}1 chain of human and sheep very late antigen-1, given 30 minutes before challenge, blocks both the allergen-induced late response and the associated airway hyperresponsiveness, functional indicators of allergen-induced inflammation, in sheep. AQC2 does not affect the early response. Consistent with these effects, AQC2 tended to reduce the cell response associated with local antigen instillation. An isotype-matched control antibody had no protective effects. Two humanized versions of AQC2, a wild-type IgG1 and an aglycosyl form of the same monoclonal antibody, which has reduced Fc receptor–mediated effector functions, are equally effective in blocking the antigen-induced late response and airway hyperresponsiveness in the sheep model. These data suggest that mononuclear leukocyte adhesion–dependent pathologies contribute to allergic lung disease and provide proof-of-concept that antagonists of {alpha}1 integrins may be useful in preventing these events.

Key Words: asthma • inflammation • integrin • animal model • CD49a




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