MUCOSAL IL-12 GENE DELIVERY INHIBITS ALLERGIC AIRWAYS DISEASE AND RESTORES LOCAL ANTIVIRAL IMMUNITY

Allergic asthma strongly correlates with airways inflammation driven b y interleukin (IL)-4 and IL-5 secreted by allergen-specific CD4(+) T c ells. it is possible that over-production of these factors in the lung s may render asthmatic individuals less able to resolve virus infectio n of the respiratory tract by down-regulating type 1 cytokine-driven i mmune responses. IL-12 is important for the establishment of cell-medi ated immunity (CMI) and may also inhibit responses driven by type 2 cy tokine production. Sustained expression of IL-12 in the airways may, t herefore, represent an effective preventive treatment or therapy for a llergic asthma and any adverse consequences of excessive production of type 2 cytokines for the development of local CMI. Here, we show that allergic responses in airways profoundly inhibit the development of a ntiviral CMI in mice following local immunization with vaccinia virus (VV) leading to persistent lung infection. However, mucosal gene trans fer of IL-12 in the lung, via a VV vector, inhibited local type 2 cyto kine production, both prevented the development of allergic disease an d airways hyperreactivity in a manner largely dependent on endogenous interferon-gamma expression and suppressed established allergic diseas e, and reversed the suppression of local antiviral CMI responses resul ting in rapid resolution of virus infection. Our study provides the fi rst direct demonstration that allergic conditions, particularly in air ways, may inhibit immune responses to concomitant virus infection and suggests that transient mucosal IL-12 gene therapy represents an effec tive approach to both the prevention and treatment of allergic airways disease and associated immunosuppression of CMI.