The effect of R 15.7/HO an anti-CD18 antibody on the late airway response and airway hyperresponsiveness in an allergic rabbit model

摘要

class="enumerated" style="list-style-type:decimal">The effects of a mouse (IgG1 fraction) anti-CD 18 neutralizing antibody (R15.7) on allergen-induced late airway response (LAR), airway hyperresponsiveness (AHR) and cellular recruitment were investigated in an allergic rabbit model.Litter-matched NZW rabbits immunized within 24 h of birth with Alternaria tenuis (i.p.) and subsequently exposed to the allergen (i.p.) for the first 3 months of life were challenged with inhaled allergen as adult rabbits. Lung function in terms of dynamic compliance (Cdyn; ml cmH2O⁻¹) and total lung resistance (RL; cmH2O⁻¹ s⁻¹) was monitored for 6 h following the allergen challenge. On day 16, separate groups of rabbits were pretreated with either control antibody (a non-binding mouse IgG1, 1 mg kg⁻¹, i.v.) or R15.7 (1 mg kg⁻¹, i.v.) and 1 h later all were challenged with Alternaria tenuis and lung function monitored thereafter. Airway responsiveness to inhaled histamine was assessed by measuring RL and Cdyn 24 h before and after allergen challenge and bronchoalveolar lavage (BAL) was also performed 24 h before and after allergen challenge.Pretreatment of rabbits with the control antibody had no effect on the LAR as measured by AUC (Cdyn, 0–6 h). However, the magnitude of the LAR following treatment with R15.7 was significantly reduced when compared to LAR demonstrated on 1st challenge (P<0.001) or to that of the control group on both challenges (P<0.01).In control antibody pretreated rabbits allergen induced a significant 3.4 fold reduction in the PC50 response to inhaled histamine in terms of RL changes (P<0.05) and a significant 2.1 fold reduction in PC35 response to inhaled histamine in terms of Cdyn changes (P<0.05). However, in anti-CD 18 antibody pretreated rabbits there was no significant change in responsiveness to histamine 24 h following allergen, as assessed by either RL PC50 or Cdyn PC₃₅.Allergen challenge induced a significant increase in eosinophil and neutrophil numbers (P<0.05) in rabbits pre-treated with control antibody, whereas treatment with R15.7 significantly inhibited this increase in the numbers of both cell types.This study demonstrates that the neutralization of CD-18 molecules reduces allergen-induced infiltration of both eosinophils and neutrophils into the airways and abolishes the accompanying LAR and AHR. These results provide evidence to support a role for CD-18 adhesion molecules in the transmigration of inflammatory cells into airways.