IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice

Abstract

In the present study, we examined the preventive effect of anti-mouse IL-6 receptor (IL-6R) antibody, MR16-1, on the development of autoimmune kidney disease in female NZB/W F1 (BWF1) mice. Immunological tolerance to MR16-1 or isotype-matched control antibody, KH-5, was induced by the simultaneous administration of anti-CD4 MoAb in mice. Thereafter, mice were intraperitoneally given 0.5 mg of MR16-1, 0.5 mg of KH-5 or saline once a week from 13 to 64 weeks of age. MR16-1 treatment dramatically suppressed proteinuria and prolonged the survival time of BWF1 mice. Only one out of 10 mice died with high levels of proteinuria throughout the experiment. MR16-1 almost completely suppressed the production of IgG forms of anti-DNA and anti-TNP antibodies, but not the IgM forms of these antibodies. In particular, all IgG subclasses (IgG1, IgG2a, IgG2b and IgG3) of anti-DNA antibody production were significantly suppressed. Moreover, serum IgG1, IgG2a and IgG3 levels in MR16-1-treated mice were lower than those in saline- and KH-5-treated mice, whereas serum IgM and IgA levels were not influenced. In conclusion, MR16-1 potently suppressed the development of autoimmune disease in BWF1 mice, and this was attributed to its effect of specific suppression of IgG class antibody production.

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

“…These studies emphasize the importance of steady-state levels of IL-6 for responses to infection, as well as the ability of IL-6 to cause severe immunopathology when expressed at high levels. Given the long association between IL-6 and SLE (36,37,(46)(47)(48)(49), it is surprising that there are very few studies that have targeted the IL-6 axis in SLE, and no significant clinical trials using anti-IL-6 (tocilizumab), even though targeting of IL-6 has been shown to be successful in the treatment of autoimmune-prone animals (50)(51)(52). This is particularly surprising given that therapies targeting IL-6 have been shown to be very effective in the treatment of other autoimmune diseases such as rheumatoid arthritis (53)(54)(55).…”

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

“…60 Antibodies were applied in doses previously shown to be effective, including anti-IL-6R (750 mg, MR16-1; provided by Chugai Pharmaceutical Co. Ltd., Tokyo, Japan 33 ), anti-IL-6 (500 mg, MP5-20F3), and sgp130Fc (250 mg), 61 or control antibodies (750 mg rat IgG for MR16-1 or 500 mg hIgG for anti-IL-6 and sgp130Fc) were intraperitoneally injected 24 hours before and 5 days after NTN induction. For aNTN, 41 mice were preimmunized with sheep IgG in complete Freund's adjuvant at day 5.…”

“…32 Application of anti-IL-6R as well as anti-IL-6 antibodies were subsequently shown to ameliorate disease by two independent groups. 33,34 Mechanistically, the deleterious effects of IL-6 were largely ascribed to production of pathogenic antibodies. Some authors also suspected IL-6 effects on T-cell activation; however, this was not addressed any further and effects on Th17 responses have not yet been studied.…”

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

“…Mice and SLE patients exhibit elevated IL-6 and inhibition of IL-6 or the IL-6 receptor decreases anti-dsDNA and proteinuria. [73][74][75] With HSP90 inhibition by GA, IL-6 expression was reduced in macrophages by preventing HSP90 from chaperoning newly transcripted cytokines. 76 HSP90 complexes with iNOS and is required for iNOS to synthesize NO.…”