TY - JOUR
T1 - IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease
AU - Bossù, Paola
AU - Neumann, Detlef
AU - Del Giudice, Elda
AU - Ciaramella, Antonio
AU - Gloaguen, Isabelle
AU - Fantuzzi, Giamila
AU - Dinarello, Charles A.
AU - Di Carlo, Emma
AU - Musiani, Piero
AU - Meroni, Pier Luigi
AU - Caselli, Gianfranco
AU - Ruggiero, Paolo
AU - Boraschi, Diana
PY - 2003/11/25
Y1 - 2003/11/25
N2 - The lupus-like autoimmune syndrome of MRL/Mp-Tnfrsf6Ipr (Ipr) 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-γ plays a pivotal role in the abnormal cell activation and the fatal development of the Ipr disease. IL-18, an inducer of IFN-γ in T lymphocytes and natural killer cells, may contribute to the disease because cells from Ipr 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 Ipr 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-γ 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 Ipr mice and that a reduction in IL-18 activity could be a therapeutic strategy in autoimmune diseases.
AB - The lupus-like autoimmune syndrome of MRL/Mp-Tnfrsf6Ipr (Ipr) 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-γ plays a pivotal role in the abnormal cell activation and the fatal development of the Ipr disease. IL-18, an inducer of IFN-γ in T lymphocytes and natural killer cells, may contribute to the disease because cells from Ipr 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 Ipr 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-γ 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 Ipr mice and that a reduction in IL-18 activity could be a therapeutic strategy in autoimmune diseases.
UR - http://www.scopus.com/inward/record.url?scp=10744222448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=10744222448&partnerID=8YFLogxK
U2 - 10.1073/pnas.2336094100
DO - 10.1073/pnas.2336094100
M3 - Article
C2 - 14615579
AN - SCOPUS:10744222448
VL - 100
SP - 14181
EP - 14186
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - SUPPL. 2
ER -