Mucosal IL-12 gene delivery inhibits allergic airways disease and restores local antiviral immunity.
Allergic asthma strongly correlates with airways inflammation driven by interleukin (IL)-4 and IL-5 secreted by allergen-specific CD4+ T cells. It is possible that over-production of these factors in the lungs may render asthmatic individuals less able to resolve virus infection of the respiratory tract by down-regulating type 1 cytokine-driven immune responses. IL-12 is important for the establishment of cell-mediated immunity (CMI) and may also inhibit responses driven by type 2 cytokine production. Sustained expression of IL-12 in the airways may, therefore, represent an effective preventive treatment or therapy for allergic 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 antiviral CMI in mice following local immunization with vaccinia virus (VV) leading to persistent lung infection. However, mucosal gene transfer of IL-12 in the lung, via a VV vector, inhibited local type 2 cytokine production, both prevented the development of allergic disease and airways hyperreactivity in a manner largely dependent on endogenous interferon-gamma expression and suppressed established allergic disease, and reversed the suppression of local antiviral CMI responses resulting in rapid resolution of virus infection. Our study provides the first direct demonstration that allergic conditions, particularly in airways, may inhibit immune responses to concomitant virus infection and suggests that transient mucosal IL-12 gene therapy represents an effective approach to both the prevention and treatment of allergic airways disease and associated immunosuppression of CMI.
Hogan
S P
SP
Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra.
Foster
P S
PS
Tan
X
X
Ramsay
A J
AJ
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000378:metabolism / Q000627:therapeutic use; D018928:Immunity, Mucosal / Q000235:genetics*; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014615:Vaccinia / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
D000914:Antibodies, Viral; D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma