Published online before print November 13, 2003, 10.1073/pnas.2336094100
PNAS | January 1, 1990 | vol. 0 | no. 2003 | 233609410-0

Immunology
IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease

Paola Bossù , Detlef Neumann +, Elda Del Giudice , Antonio Ciaramella , Isabelle Gloaguen °, Giamila Fantuzzi \, Charles A. Dinarello \, Emma Di Carlo |, Piero Musiani |, Pier Luigi Meroni **, Gianfranco Caselli , Paolo Ruggiero #, and Diana Boraschi 

*Laboratory of Clinical and Behavioral Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00179 Rome, Italy; ⁺Department of Pharmacology, Hannover Medical School, 30623 Hannover, Germany; Research Center Dompé SpA, 67100 L’Aquila, Italy;°Consorzio Biolaq, 67100 L’Aquila, Italy; ^\Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; ^|Department of Oncology and Neurosciences, University of Chieti, 66100 Chieti, Italy; ^**Department of Internal Medicine, University of Milan, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, 20122 Milan, Italy; ^#Research Center Chiron SpA, 53100 Siena, Italy; and Institute of Biomedical Technologies, Consiglio Nazionale delle Ricerche, 56124 Pisa, Italy

Contributed by Charles A. Dinarello, September 22, 2003

The lupus-like autoimmune syndrome of MRL/Mp-Tnfrsf6^lpr (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- plays a pivotal role in the abnormal cell activation and the fatal development of the lpr disease. IL-18, an inducer of IFN- 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- 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.

www.pnas.org/cgi/doi/10.1073/pnas.2336094100