Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis by counter-regulation of autoreactive Th1 responses to peripheral myelin antigen

Experimental autoimmune neuritis (EAN) is a demyelinating disease of the peripheral nervous system (PNS). This acute inflammatory disease is mediated by CD4(-) T cells and bears significant similarities to the Guillain-Barre syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoinnniunity of FAN in [nice induced by PO peptide 180-199 and Freund's complete adjuvant. Our data indicate chat in 2 different therapeutic regimens. anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs alpha EAN. The suppression is associated with reduced inflammatory cell infiltration into the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a reduced mononuclear cell proliferation and IFN-gamma-secretion in the spleen. Increased numbers of IL-4 expressing cells and decreased numbers of IFN-gamma and TNF-alpha expressing cells were found in the PNS. Our results, suggest that,hitting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAh. In addition, anti-IL-18 mAb treatment reduced anti-PO peptide 180-199 autoantibody responses, which may also contribute to EAN suppression. we conclude that endogenous IL-18 plays a critical role in the pathogenesis of autoimmune demyelinating disease of the PNS and that IL-18 antagonists may provide a new therapy for these diseases.