Injection of IL-12- and IL-18-encoding plasmids ameliorates the autoimmune pathology of MRL/Mp-Tnfrsf6lpr mice: synergistic effect on autoimmune symptoms.
IL-12 and IL-18 are mediators involved in the onset and progression of the autoimmune disease developing in MRL/Mp-Tnfrsf6(lpr) (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 IFNgamma and tumor necrosis factor-alpha (TNFalpha). 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 TNFalpha and reduced the ability of lymphocytes from treated mice to produce IFNgamma 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 T(h)1-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.
Neumann
Detlef
D
Department of Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. neumann.detlef@mh-hannover.de
Tschernig
Thomas
T
Popa
Daniela
D
Schmiedl
Andreas
A
Pérez de Lema
Guillermo
G
Resch
Klaus
K
Martin
Michael Uwe
MU
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D018076:DNA, Complementary; D005260:Female; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009929:Organ Size; D010957:Plasmids; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019444:Vaccines, DNA / Q000008:administration & dosage
D018076:DNA, Complementary; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D018664:Interleukin-12