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

1 The effects of a mouse (IgG(1) fraction) anti-CD18 neutralizing antibody (R15.7) on allergen-induced late airway response (LAR), airway hyperresponsiveness (AHR) and cellular recruitment were investigated in an allergic rabbit model. 2 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 (C-dyn; ml cmH(2)O(-1)) and total lung resistance (R-L; cmH(2)O(-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 IgG(1), 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 R-L and C-dyn 24 h before and after allergen challenge and bronchoalveolar lavage (BAL) was also performed 24 h before and after allergen challenge. 3 Pretreatment of rabbits with the control antibody had no effect on the LAR as measured by AUC (C-dyn, 0-6 h) However, the magnitude of the LAR following treatment with R15.7 was significantly reduced when compared to LAR demonstrated on Ist challenge (P<0.001) or to that of the control group on both challenges (P<0.01). 4 In control antibody pretreated rabbits allergen induced a significant 3.4 fold reduction in the PC50 response to inhaled histamine in terms of R-L changes (P<0.05) and a significant 2.1 fold reduction in PC35 response to inhaled histamine in terms of C-dyn changes (P<0.05). However, in anti-CD18 antibody pretreated rabbits there was no significant change in responsiveness to histamine 24 h following allergen, as assessed by either R-L PC50 or C-dyn PC35. 5 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. 6 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.