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Originally published online as doi:10.1189/jlb.0604325 on August 17, 2004

Published online before print August 17, 2004
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(Journal of Leukocyte Biology. 2004;76:1028-1038.)
© 2004 by Society for Leukocyte Biology

Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization

Harmjan Kuipers*,1, Carlo Heirman{dagger}, Daniëlle Hijdra*, Femke Muskens*, Monique Willart*, Sonja van Meirvenne{dagger}, Kris Thielemans{dagger}, Henk C. Hoogsteden* and Bart N. Lambrecht*

* Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands; and
{dagger} Laboratory of Physiology, Medical School of Vrije Universiteit Brussel, Brussels, Belgium

1 Correspondence: Erasmus MC, Department of Pulmonary Medicine, Room Ee2263, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: h.kuipers{at}erasmusmc.nl

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 naïve 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.

Key Words: gene therapy • inflammation




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