The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/5/1671/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 9, May 5, 1997 1671-1680

Articles

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

Shogo Tsuyuki{ddagger}, Junko Tsuyuki*, Karin Einsle*, Manfred Kopf§, and Anthony J. Coyle*

From * Ciba-Geigy Ltd., Asthma and Allergy Research Department, Pharmaceutical Division, CH-4002 Basel, Switzerland; {ddagger} R&D Dept. Kissei Pharmaceutical Co. Ltd., Matsumoto, 399, Japan; § Basel Institute for Immunology, CH-4005 Basel, Switzerland

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.

Address correspondence to Dr. Anthony J. Coyle, Department of Experimental Therapeutics, Millennium Pharmaceuticals, Cambridge, MA 02139-4815.

1Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; MCh, methacholine.


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