title: Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness.
abstract: The recruitment of eosinophils into the airways after allergen exposure is dependent on interleukin (IL) 5 secreted from antigen-specific CD4+ T cells of the T helper cell (Th) 2 subset. However, while it is established that costimulation through CD28 is required for TCR-mediated activation and IL-2 production, the importance of this mechanism for the induction of a Th2 immune response is less clear. In the present study, we administered the fusion protein CTLA-4 immunoglobulin (Ig) into the lungs before allergen provocation to determine whether CD28/CTLA-4 ligands are required for allergen-induced eosinophil accumulation and the production of Th2 cytokines. Administration of CTLA-4 Ig inhibited the recruitment of eosinophils into the lungs by 75% and suppressed IgE in the bronchoalveolar lavage fluid. CTLA-4 Ig also inhibited the production of IL-4, IL-5, and IL-10 by 70-80% and enhanced interferon-gamma production from CD3-T cell receptor-activated lung Thy1.2+ cells. Allergen exposure upregulated expression of B7-2, but not B7-1, on B cells from the lung within 24 h. Moreover, airway administration of an anti-B7-2 monoclonal antibody (mAb) inhibited eosinophil infiltration, IgE production, and Th2 cytokine secretion comparable in magnitude to that observed with CTLA-4 Ig. Treatment with an anti-B7-1 mAb had a small, but significant effect on eosinophil accumulation, although was less effective in inhibiting Th2 cytokine production. The anti-B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyperresponsiveness in vivo. In all of the parameters assessed, the combination of both the anti-B7-1 and anti-B7-2 mAb was no more effective than anti-B7-2 mAb treatment alone. We propose that strategies aimed at inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic inflammation.
authors.affiliation: R&D Dept. Kissei Pharmaceutical Co. Ltd., Matsumoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tsuyuki
authors.forename: J
authors.initials: J
authors.lastname: Tsuyuki
authors.forename: K
authors.initials: K
authors.lastname: Einsle
authors.forename: M
authors.initials: M
authors.lastname: Kopf
authors.forename: A J
authors.initials: AJ
authors.lastname: Coyle
mesh_terms: D000069594:Abatacept; D000485:Allergens; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000494:pharmacology; D018122:B7-1 Antigen / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology; D018928:Immunity, Mucosal; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D012123:Pulmonary Ventilation; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000485:Allergens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D007073:Immunoglobulin E; D000069594:Abatacept; D007371:Interferon-gamma