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International Immunology Advance Access originally published online on October 31, 2006
International Immunology 2006 18(12):1779-1787; doi:10.1093/intimm/dxl112
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Injection of IL-12- and IL-18-encoding plasmids ameliorates the autoimmune pathology of MRL/Mp-Tnfrsf6lpr mice: synergistic effect on autoimmune symptoms

Detlef Neumann1, Thomas Tschernig2, Daniela Popa2, Andreas Schmiedl3, Guillermo Pérez de Lema4, Klaus Resch1 and Michael Uwe Martin1,5

1 Department of Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
2 Department of Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
3 Department of Microscopic Anatomy, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
4 Ludwig-Maximilians-University, Medizinische Poliklinik, D-80336 Munich, Germany
5 Present address: Institute of Immunology, Justus-Liebig-University, Winchesterstrasse 2, D-35394 Giessen, Germany

Correspondence to: D. Neumann; E-mail: neumann.detlef{at}mh-hannover.de

IL-12 and IL-18 are mediators involved in the onset and progression of the autoimmune disease developing in MRL/Mp-Tnfrsf6lpr (lpr) mice, which display symptoms similar to the human systemic lupus erythematosus (SLE). The pathology is characterized by progressive lymphadenopathy and auto-antibody-mediated multiple organ failure, e.g. glomerulonephritis, or pneumonitis and a concomitant increase in serum levels for IFN{gamma} and tumor necrosis factor-{alpha} (TNF{alpha}). In this study, we intramuscularly injected lpr mice with plasmids encoding IL-12 and IL-18, either alone or in combination, in order to affect the development of the autoimmune disease. Five biweekly injections of the combined plasmids starting at 4–5 weeks of age diminished serum levels of TNF{alpha} and reduced the ability of lymphocytes from treated mice to produce IFN{gamma} in vitro. Injection of both plasmids synergistically attenuated the development of autoimmune syndromes, lymphoproliferation in secondary lymphoid organs, proteinuria and kidney damage, and pneumonitis. We conclude that IL-12 and IL-18 synergistically affect the pathogenesis of the Th1-dependent autoimmune syndrome of lpr mice and that approaches that target both IL-12 and IL-18 may be a therapeutic option in the treatment of autoimmune SLE.

Keywords: autoimmunity, cytokines, kidney, lupus, lymph node

Transmitting editor: T. Huenig


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