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* Institute of Microbiology and Hygiene, Department of Infection Immunology and
Department of Gastroenterology, Charité-University Medicine Berlin, Berlin;
Department of Infection Pathology and
Department of Virology and Immunology, German Primate Center, Göttingen;
¶ Department of Pathology, Bernhard Nocht Institute for Tropical Medicine, Hamburg; and
|| Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
Experimental studies in monkeys on the basis of ex vivo-generated, reinjected dendritic cells (DCs) allow investigations of primate DC biology in vivo. To study in vitro and in vivo properties of DCs with a reduced capacity to produce IL-12, we adapted findings obtained in vitro with human cells to the rhesus macaque model. Following exposure of immature monocyte-derived monkey DCs to the immunomodulating synthetic polypeptide glatiramer acetate (GA) and to dibutyryl-cAMP (d-cAMP; i.e., a cAMP enhancer that activates DCs but inhibits the induction of Th1 immune responses), the resulting DCs displayed a mature phenotype with enhanced Ag-specific T cell stimulatory function, notably also for memory Th1 cells. Phosphorylation of p38 MAPK was not induced in GA/d-cAMP-activated DCs. Accordingly, these cells secreted significantly less IL-12p40 (p 
0.001) than did cytokine-activated cells. However, upon restimulation with rhesus macaque CD154, GA/d-cAMP-activated DCs produced IL-12p40/IL-23. Additionally, DCs activated by proinflammatory cytokines following protocols for the generation of cells used in clinical studies secreted significantly more IL-23 upon CD154 restimulation than following prior activation. Two days after intradermal injection, GA/d-cAMP-activated fluorescence-labeled DCs were detected in the T cell areas of draining lymph nodes. When similarly injected, GA/d-cAMP as well as cytokine-activated protein-loaded DCs induced comparable Th immune responses characterized by secretion of IFN-
, TNF, and IL-17, and transiently expanded FOXP3+ regulatory T cells. Reactivation of primate DCs through CD154 considerably influences their immmunostimulatory properties. This may have a substantial impact on the development of innovative vaccine approaches.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the German Research Foundation (Klinische Forschergruppe 104 to R.I. and T.S., and IG 14/3-1 to R.I.), by the European Union Grant 018685 to K.T.R., C.S.H., P.R., K.Ü., and R.I., and the H.W. & J. Hector Foundation (to R.I.).
2 E.J. and M.E. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ralf Ignatius, Institute of Microbiology and Hygiene, Department of Infection Immunology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, 12203 Berlin, Germany. E-mail address: ralf.ignatius{at}charite.de
4 Abbreviations used in this paper: DC, dendritic cell; BCG, Mycobacterium bovis bacillus Calmette-Guérin; CMFDA, 5-chloromethylfluorescein diacetate; d-cAMP, dibutyryl-cAMP; GA, glatiramer acetate; KLH, keyhole limpet hemocyanin; PPD, purified protein derivative of Mycobacterium tuberculosis; SEB, staphylococcal enterotoxin B.
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