title: The effect of anti-integrin monoclonal antibodies on antigen-induced pulmonary inflammation in allergic rabbits.
abstract: The integrin adhesion molecules are involved in the recruitment and activation of inflammatory cells at sites of inflammation in a variety of diseases. In the present study, we have investigated the effects of blocking monoclonal antibodies (mAbs) directed against CD49d (alpha(4) integrin), CD18 (beta(2) integrin) and the alpha sub-units of beta(2) integrin CD11a (LFA-1 integrin) and CD11b (Mac-1 integrin), on antigen (Ag)-induced acute bronchoconstriction and cellular recruitment in allergic rabbits in vivo. Inhaled Ag (Alternaria tenuis) challenge of neonatally sensitised rabbits caused an acute bronchoconstriction demonstrated by an increase in lung resistance (R(L)) and decrease in dynamic compliance (C(dyn)) and pulmonary inflammation characterised by an increase in bronchoalveolar lavage (BAL) inflammatory cells, particularly eosinophils, 24 h after challenge. Pre-treatment with the anti-CD49d mAb (Max-68P), significantly inhibited the Ag-induced acute bronchoconstriction in terms of R(L) and (C(dyn)). Treatment with the other anti-integrin mAbs had no effect on the acute bronchoconstriction after inhaled Ag challenge.Pre-treatment with the anti-integrin mAbs had differential effects in blocking the recruitment of inflammatory cells 24 h after inhaled Ag in the allergic rabbits. The data show that in the allergic rabbit model of asthma, VLA-4 (CD49d/CD29) only, is involved in the acute bronchoconstriction, suggesting an involvement of mast cell degranulation. Furthermore, eosinophil recruitment and activation appears to be mediated by a combination of VLA-4 (CD49d/CD29) and LFA-1 (CD18/CD11a). However in contrast, lymphocyte recruitment appears to be mediated by a combination of LFA-1 (CD18/CD11a) and Mac-1 (CD18/CD11b).
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, GKT School of Biomedical Sciences, 5th Floor, Hodgkin Building, Guy's Campus, King's College London, SE1 9RF, London, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Gascoigne
authors.forename: K
authors.initials: K
authors.lastname: Holland
authors.forename: C P
authors.initials: CP
authors.lastname: Page
authors.forename: A
authors.initials: A
authors.lastname: Shock
authors.forename: M
authors.initials: M
authors.lastname: Robinson
authors.forename: R
authors.initials: R
authors.lastname: Foulkes
authors.forename: N
authors.initials: N
authors.lastname: Gozzard
mesh_terms: D000402:Airway Obstruction / Q000209:etiology / Q000276:immunology*; D000528:Alternaria / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000502:physiology*; D000946:Antigens, Fungal / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction / Q000276:immunology; D040881:CD11a Antigen / Q000187:drug effects / Q000276:immunology; D039481:CD11b Antigen / Q000187:drug effects / Q000276:immunology; D018821:CD18 Antigens / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000009:adverse effects* / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D047209:Eosinophil Peroxidase; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D005260:Female; D039441:Integrin alpha4 / Q000187:drug effects / Q000276:immunology; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D010544:Peroxidases / Q000737:chemistry; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology*; D011817:Rabbits; D015293:Transducin / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D040881:CD11a Antigen; D039481:CD11b Antigen; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D039441:Integrin alpha4; D047209:Eosinophil Peroxidase; D010544:Peroxidases; D015293:Transducin