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-Barré syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide 180-199 and Freund's complete adjuvant. Our data indicate that in 2 different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs of 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 shifting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAb. In addition, anti-IL-18 mAb treatment reduced anti-P0 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.
Yu
Shuo
S
Department of NEUROTEC, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Chen
Zhiguo
Z
Mix
Eilhard
E
Zhu
Shun-Wei
SW
Winblad
Bengt
B
Ljunggren
Hans-Gustaf
HG
Zhu
Jie
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D001323:Autoantibodies / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D020275:Guillain-Barre Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007150:Immunohistochemistry; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018993:Myelin P0 Protein / Q000276:immunology*; D009444:Neuritis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology; D010525:Peripheral Nerves / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D020382:Interleukin-18; D018993:Myelin P0 Protein; D010446:Peptide Fragments