title: The effects of interleukin-6 signal blockade on immune system, reproductive and skeletal development in juvenile mice.
abstract: Interleukin-6 (IL-6) is involved in the pathogenesis of multiple disorders, including juvenile autoimmune diseases. IL-6 participates in a broad spectrum of physiological events, and the IL-6 receptor (IL-6R) is widely distributed across multiple organs. The interrelationship of development phases in juveniles together with organs involved in IL-6 signaling called for evaluations of anti-IL-6R antibody induced effects in a juvenile mouse model to assess the safety of such an approach in human juvenile arthritis. Here we show that naive mice in which IL-6 signals have been transiently blocked during the juvenile period develop normally. The fatal immunogenic reactions recorded earlier by repeated administration of the chosen rat anti-mouse IL-6R antibody, MR16-1, to mice were avoided successfully by application of a high loading dose followed by lower maintenance doses, with the support of modeling data. The high loading-dose regimen enabled us to conduct assessments without any major interference due to immunogenicity. Transient and complete inhibition of IL-6 signals from postnatal days 22 to 79 in mice exhibited no biologically important changes in sexual maturation or development of immune and skeletal systems. Although tendencies toward reductions of peripheral blood T-cell counts were observed, normal levels of antigen-specific IgG/IgM antibody productions indicating sufficient immunological functions were confirmed. Our results demonstrate that blockage of IL-6R by the neutralizing antibody does not affect juvenile development. This may be in part due to the generation or existence of compensatory pathways in the whole body system.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan. sakuraitky@chugai-pharm.co.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakurai
authors.forename: Ryo
authors.initials: R
authors.lastname: Takai
authors.forename: Heinrich
authors.initials: H
authors.lastname: Bürgin
authors.forename: Akifumi
authors.initials: A
authors.lastname: Shioda
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Amano
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Grimm
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Richter
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Chiba
authors.forename: Akinori
authors.initials: A
authors.lastname: Kawamura
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Lutz
authors.initials: L
authors.lastname: Müller
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000276:immunology; D001842:Bone and Bones / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007107:Immune System / Q000187:drug effects* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D012098:Reproduction / Q000187:drug effects*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015850:Interleukin-6; D019947:Receptors, Interleukin-6