Blockade of CD49d inhibits allergic airway pathologies independent of effects on leukocyte recruitment.
Lymphocyte and/or eosinophil recruitment is dependent on the sequential interactions between adhesion molecules expressed on activated endothelial cells and both leukocyte subtypes. Endothelial P- and E-selectins mediate tethering and rolling of leukocytes through interactions with P-selectin glycoprotein ligand-1 (PSGL-1), and diapedesis subsequently occurs by engagement of endothelial vascular cell adhesion molecule-1 and CD49d (alpha(4)-integrins). The anti-inflammatory potential of interfering with these adhesive interactions was assessed with an ovalbumin challenge mouse model of asthma. Administration of a soluble form of PSGL-1 reduced eosinophils (80%) and lymphocytes (50%) in bronchoalveolar lavage fluid without affecting epithelial changes or airway hyperreactivity (AHR). In contrast, although administration of anti-CD49d monoclonal antibodies (PS/2) resulted in similar reductions in eosinophils (75%) and lymphocytes (50%), PS/2 reduced and abolished mucous cell metaplasia and AHR, respectively. Administration of both PSGL-1 and PS/2 had the additive effect of eliminating eosinophils from the airways (96% decrease), with few or no additional reductions (relative to PS/2 administration alone) in lymphocyte recruitment, mucous cell metaplasia, or AHR. These data show that eosinophils and lymphocytes differentially utilize adhesive interactions during recruitment and that the inhibition of AHR is independent of this recruitment.
Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, 13400 E. Shea Blvd., Scottsdale, AZ 85259, USA.
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Borchers
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Crosby
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Farmer
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Sypek
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Ansay
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Lee
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JJ
Lee
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D001773:Blood Cells / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000517:prevention & control; D004338:Drug Combinations; D004802:Eosinophilia / Q000473:pathology; D005260:Female; D006967:Hypersensitivity / Q000150:complications*; D039441:Integrin alpha4; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology*; D008168:Lung / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology; D012995:Solubility
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004338:Drug Combinations; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011994:Recombinant Proteins; D039441:Integrin alpha4