B7-CD28 CTLA-4 COSTIMULATORY PATHWAYS ARE REQUIRED FOR THE DEVELOPMENT OF T-HELPER CELL 2-MEDIATED ALLERGIC AIRWAY RESPONSES TO INHALED ANTIGENS/

We have previously demonstrated that the development of allergen-induc ed airway hyperresponsiveness in a murine model is CD4(+) T cell depen dent, In the present study, we examined the role of the B7/CD28-CTLA4 costimulatory T cell activation pathway in the pathogenesis of allerge n-induced airway hyperresponsiveness in this murine model, Sensitized A/J mice develop significant increases in airway responsiveness, bronc hoalveolar lavage eosinophils, serum IgE levels, and Th2-associated cy tokine production following aspiration challenge with OVA, Administrat ion of CTLA4-Ig either before Ag sensitization or before pulmonary Ag challenge abolished Ag-induced airway hyperresponsiveness and pulmonar y eosinophilia, Examination of cytokine protein levels in the bronchoa lveolar lavage showed a significant decrease in the level of the Th2 c ytokine, IL-4, after CTLA4-Ig treatment either before sensitization or before challenge, with no significant change in the concentration of the Th1 cytokine, IFN-gamma. Further, the Ag-specific Ab isotypes IgG1 and IgE were significantly decreased in animals treated with CTLA4-Ig before challenge, while there was no significant change in the IgG2a Ab isotype, These data demonstrate that administration of CTLA4-Ig is effective in ablating allergen-induced airway dysfunction concomitant with a significant reduction in the Th2 response, We conclude that B7/ CD28-CTLA-4 costimulation is required for the development of many of t he immunologic and physiologic features of asthma, possibly by promoti ng a pathologic type 2-associated response.