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* Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium;
Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium;
Center for Transgene Technology & Gene Therapy, University of Leuven, Leuven, Belgium;
Department of Transgene Technology and Gene Therapy, Vlaams Instituut voor Biotechnologie, Leuven, Belgium;
¶ Cell and Tissue Laboratory, Unité de Recherche en Physiologie Moléculaire, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium; and
|| Institut de Biologie et Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium
Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes to TIP-DCs and protects the host from tissue damage.
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1 This work was supported by research funding from the Fund for Scientific Research Flanders (Fonds Wetenschappelijk Onderzoek-Vlaanderen), the Institute for Promotion of Innovation by Science and Technology in Flanders (Innovative door Wetenschapen Technologie-Vlaanderen), and Flanders Institute for Biotechnology (Vlaams Instituut voor Biotechnologie) to M.G., K.M., and T.B. and was performed in frame of an Interuniversity Attraction Pole Program. M.M. is a senior research associate from Fonds National de la Recherche Scientifique.
2 Address correspondence and reprint requests to Dr. Alain Beschin, Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Building E, Pleinlaan 2, 1050 Brussels, Belgium. E-mail address: abeschin{at}vub.ac.be
3 Abbreviations used in this paper: KO, knockout; iNOS, inducible NO synthase; MHC-I/-II, MHC class I/class II; ALT, alanine aminotransferase; AAV, adeno-associated viral; TIP-DC, TNF/iNOS-producing dendritic cell; WT, wild type.
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