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International Immunology Advance Access published online on October 31, 2006
International Immunology, 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
Received May 6, 2005
Accepted September 25, 2006

Article

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

Detlef Neumann 1 *, Thomas Tschernig 2, Daniela Popa 2, Andreas Schmiedl 3, Guillermo Pérez de Lema 4, Klaus Resch 1, and Michael Uwe Martin 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 Department of Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; Present address: Institute of Immunology, Justus-Liebig-University, Winchesterstrasse 2, D-35394 Giessen, Germany

* To whom correspondence should be addressed.
Detlef Neumann, E-mail: neumann.detlef{at}mh-hannover.de


  Abstract

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.
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