MURINE CTLA4-IGG TREATMENT INHIBITS AIRWAY EOSINOPHILIA AND HYPERRESPONSIVENESS AND ATTENUATES IGE UP-REGULATION IN A MURINE MODEL OF ALLERGIC-ASTHMA

Antigen-specific T-cell activation requires the engagement of the T-ce ll receptor (TCR) with antigen as well as the engagement of appropriat e costimulatory molecules. One of the most important pathways of costi mulation is the interaction of CD28 on the T cell with B7-1/B7-2 on an tigen-presenting cells. In the present study, we have examined, the in vivo effects of blocking the CD28:B7 T-cell costimulatory pathway by administration of mCTLA4-IgG in a murine model of allergic asthma, Mic e were sensitized with ovalbumin and exposed to repeated ovalbumin inh alation challenges. In mice treated with a control antibody at the tim e of ovalbumin challenge a significant increase in the number of eosin ophils (12.8 +/- 4.3 x 10(3) cells, P < 0.05) in the bronchoalveolar l avage (BAL) fluid and airway hyperresponsiveness to methacholine (49 /- 15%, P < 0.05) was observed, In addition, serum levels of ovalbumin -specific IgE were significantly (P < 0.01) increased after ovalbumin challenge compared with saline challenge (1,133 +/- 261 experimental u nits [EU]/ml and 220 +/- 63 EU/ml, respectively). In mice treated with mCTLA4-IgG at the time of ovalbumin challenge, the infiltration of eo sinophils into BAL fluid and the development of airway hyperresponsive ness to methacholine were completely inhibited. The upregulation of ov albumin-specific IEE levels in serum was attenuated by mCTLA4-IgG trea tment. Furthermore, addition of mCTLA4-IgG to cultures of parabronchia l lymph node cells from sensitized mice inhibited the ovalbumin-induce d interleukin-4 production. These data indicate the therapeutic potent ial of blocking T-lymphocyte costimulation by CTLA4-IgG as a possible immunosuppressive treatment for patients with allergic asthma.