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

The recruitment of eosinophils into the airways after allergen exposur e is dependent on interleukin (IL) 5 secreted from antigen-specific CD 4(+) T cells of the T helper cell (Th) 2 subset. However, while it is established that costimulation through CD28 is required for TCR-mediat ed activation and IL-2 production, the importance of this mechanism fo r 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/C TLA-4 ligands are required for allergen-induced eosinophil accumulatio n and the production of Th2 cytokines. Administration of CTLA-4 Ig inh ibited the recruitment of eosinophils into the lungs by 75% and suppre ssed ISE 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 interf eron-gamma production from CD3-T cell receptor-activated lung Thy1.2cells. 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 infilt ration, IgE production, and Th2 cytokine secretion comparable in magni tude to that observed with CTLA-4 Ig. Treatment with an anti-B7-1 mAb had a small, but significant effect on eosinophil accumulation, althou gh was less effective in inhibiting Th2 cytokine production. The anti- B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyp erresponsiveness in vivo. In all of the parameters assessed, the combi nation of both the anti-B7-1 and anti-B7-2 mAb was no more effective t han anti-B7-2 mAb treatment alone. Wie propose that strategies aimed a t inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic in flammation.