Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization.
It has been postulated that low-level interleukin (IL)-12 production of antigen-presenting cells is associated with the risk of developing atopic asthma. To study the relationship between IL-12 production capacity of dendritic cells (DCs) and development of T helper type 2 (Th2) responses in the lung, we genetically engineered DCs to constutively overexpress bioactive IL-12. Retrovirally mediated overexpression of IL-12 in DCs strongly polarized naive ovalbumin (OVA)-specific CD4+ T cells toward Th1 effector cells in vitro. After intratracheal injection, OVA-pulsed IL-12-overexpressing DCs failed to induce Th2 responses in vivo and no longer primed mice for Th2-dependent eosinophilic airway inflammation upon OVA aerosol challenge, readily observed in mice immunized with sham-transfected, OVA-pulsed DCs. Analysis of a panel of cytokines and chemokines in the lung demonstrated that the lack of Th2 sensitization was accompanied by increased production of the Th1 cytokine interferon-gamma (IFN-gamma), chemokines induced by IFN-gamma, and the immunoregulatory cytokine IL-10. When Th2 priming was induced using OVA/alum prior to intratracheal DC administration, DCs constitutively expressing IL-12 were no longer capable of preventing eosinophilic airway inflammation and even enhanced it. These data show directly that high-level expression of IL-12 in DCs prevents the development of Th2 sensitization. Enhancing IL-12 production in DCs should be seen as a primary prevention strategy for atopic disorders. Enhancing IL-12 production in DCs is less likely to be of benefit in already Th2-sensitized individuals.
Kuipers
Harmjan
H
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands. h.kuipers@erasmusmc.nl
Heirman
Carlo
C
Hijdra
Daniëlle
D
Muskens
Femke
F
Willart
Monique
M
van Meirvenne
Sonja
S
Thielemans
Kris
K
Hoogsteden
Henk C
HC
Lambrecht
Bart N
BN
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D001249:Asthma / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000941:Antigens; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin