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 in the fatal development of the lpr disease. IL 18, an inducer of IFN-gamma in T lymphocytes and natural killer cells, may contibute to the disease because cells from lpr mice are hyper-sensitive 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 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.
IL-18 cDNA vaccination protect mice from spontaneous lupus-like disease
Boraschi D
2003
Abstract
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 in the fatal development of the lpr disease. IL 18, an inducer of IFN-gamma in T lymphocytes and natural killer cells, may contibute to the disease because cells from lpr mice are hyper-sensitive 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 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
