Blockade of CD49d inhibits allergic airway pathologies independent of effects on leukocyte recruitment

Lymphocyte and/ or eosinophil recruitment is dependent on the sequential in teractions between adhesion molecules expressed on activated endothelial ce lls and both leukocyte subtypes. Endothelial P- and E-selectins mediate tet hering and rolling of leukocytes through interactions with P- selectin glyc oprotein ligand-1 (PSGL-1), and diapedesis subsequently occurs by engagemen t of endothelial vascular cell adhesion molecule-1 and CD49d (alpha (4)-int egrins). The anti-inflammatory potential of interfering with these adhesive interactions was assessed with an ovalbumin challenge mouse model of asthm a. Administration of a soluble form of PSGL-1 reduced eosinophils (80%) and lymphocytes (50%) in bronchoalveolar lavage fluid without affecting epithe lial changes or airway hyperreactivity (AHR). In contrast, although adminis tration of anti-CD49d monoclonal antibodies (PS/2) resulted in similar redu ctions in eosinophils (75%) and lymphocytes (50%), PS/2 reduced and abolish ed mucous cell metaplasia and AHR, respectively. Administration of both PSG L-1 and PS/2 had the additive effect of eliminating eosinophils from the ai rways (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 uti lize adhesive interactions during recruitment and that the inhibition of AH R is independent of this recruitment.