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 (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. 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 (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. 3. 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). 4. 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. 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.
el-Hashim
A Z
AZ
Sackler Institute of Pulmonary Pharmacology, King's College, University of London.
Jacques
C A
CA
Herd
C M
CM
Lee
T H
TH
Page
C P
CP
D000528:Alternaria / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology / Q000503:physiopathology; D018893:Bronchoalveolar Lavage; D018821:CD18 Antigens / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006632:Histamine / Q000494:pharmacology*; D007249:Inflammation; D011817:Rabbits; D012130:Respiratory Hypersensitivity / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D006632:Histamine