IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease.
The lupus-like autoimmune syndrome of MRL/Mp-Tnfrsf6lpr (lpr) mice is characterized by progressive lymphadenopathy and autoantibody production, leading to early death from renal failure. Activation of T helper lymphocytes is one of the events in the pathogenesis of the disease in these mice and likely in human systemic lupus erythematosus. Among T helper lymphocyte-dependent cytokines, IFN-gamma plays a pivotal role in the abnormal cell activation and the fatal development of the lpr disease. IL-18, an inducer of IFN-gamma in T lymphocytes and natural killer cells, may contribute to the disease because cells from lpr mice are hypersensitive to IL-18 and express high levels of IL-18. To assess the contribution of IL-18 to the pathogenesis in the animal model, in vivo inhibition of IL-18 was attempted. Young lpr mice were vaccinated against autologous IL-18 by repeated administration of a cDNA coding for the murine IL-18 precursor. Vaccinated mice produced autoantibodies to murine IL-18 and exhibited a significant reduction in spontaneous lymphoproliferation and IFN-gamma production as well as less glomerulonephritis and renal damage. Moreover, mortality was significantly delayed in anti-IL-18-vaccinated mice. These studies support the concept that IL-18 plays a major role in the pathogenesis of the autoimmune syndrome of lpr mice and that a reduction in IL-18 activity could be a therapeutic strategy in autoimmune diseases.
Bossù
Paola
P
Laboratory of Clinical and Behavioral Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00179 Rome, Italy.
Neumann
Detlef
D
Del Giudice
Elda
E
Ciaramella
Antonio
A
Gloaguen
Isabelle
I
Fantuzzi
Giamila
G
Dinarello
Charles A
CA
Di Carlo
Emma
E
Musiani
Piero
P
Meroni
Pier Luigi
PL
Caselli
Gianfranco
G
Ruggiero
Paolo
P
Boraschi
Diana
D
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000494:pharmacology*
D001323:Autoantibodies; D020382:Interleukin-18; D019444:Vaccines, DNA; D007371:Interferon-gamma