The Effects of Interleukin‐6 Signal Blockade on Immune System, Reproductive and Skeletal Development in Juvenile Mice

Sakurai, Takayuki; Takai, Ryo; Bürgin, Heinrich; Shioda, Akifumi; Sakamoto, Yuichiro; Amano, Jun; Grimm, Hans Peter; Richter, Wolfgang; Higuchi, Y.; Chiba, Shuichi; Kawamura, Akinori; Suzuki, Masami; Müller, Lutz

doi:10.1002/bdrb.21053

Cited by 7 publications

(3 citation statements)

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“…All rat IgG and MR16-1-treated dKO mice were alive until 90 days of age, body weights were similar to non-treated dKO mice, and no abnormal morphologies were observed in the internal organs. A previous study also showed that there were no adverse effects of MR16-1 administration on sexual maturation or development of the immune and skeletal systems of juvenile wild-type [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice

et al. 2017

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BackgroundChronic increases in the levels of the inflammatory cytokine interleukin-6 (IL-6) in serum and skeletal muscle are thought to contribute to the progression of muscular dystrophy. Dystrophin/utrophin double-knockout (dKO) mice develop a more severe and progressive muscular dystrophy than the mdx mice, the most common murine model of Duchenne muscular dystrophy (DMD). In particular, dKO mice have smaller body sizes and muscle diameters, and develop progressive kyphosis and fibrosis in skeletal and cardiac muscles. As mdx mice and DMD patients, we found that IL-6 levels in the skeletal muscle were significantly increased in dKO mice. Thus, in this study, we aimed to analyze the effects of IL-6 receptor (IL-6R) blockade on the muscle pathology of dKO mice.MethodsMale dKO mice were administered an initial injection (200 mg/kg intraperitoneally (i.p.)) of either the anti-IL-6R antibody MR16-1 or an isotype-matched control rat IgG at the age of 14 days, and were then given weekly injections (25 mg/kg i.p.) until 90 days of age.ResultsTreatment of dKO mice with the MR16-1 antibody successfully inhibited the IL-6 pathway in the skeletal muscle and resulted in a significant reduction in the expression levels of phosphorylated signal transducer and activator of transcription 3 in the skeletal muscle. Pathologically, a significant increase in the area of embryonic myosin heavy chain-positive myofibers and muscle diameter, and reduced fibrosis in the quadriceps muscle were observed. These results demonstrated the therapeutic effects of IL-6R blockade on promoting muscle regeneration. Consistently, serum creatine kinase levels were decreased. Despite these improvements observed in the limb muscles, degeneration of the diaphragm and cardiac muscles was not ameliorated by the treatment of mice with the MR16-1 antibody.ConclusionAs no adverse effects of treatment with the MR16-1 antibody were observed, our results indicate that the anti-IL-6R antibody is a potential therapy for muscular dystrophy particularly for promoting skeletal muscle regeneration.Electronic supplementary materialThe online version of this article (10.1186/s13395-017-0140-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice

et al. 2017

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“…Although the testis and placenta play different roles in prenatal regulation of steroidogenesis in humans and rodents ( Scott et al 2009 ), the present study supports the hypothesis that vascular disruption is a key event in MRDT, similar to pregnancy loss and other birth defects ( Abe et al 2013 ; Kleinstreuer et al 2011 ; Morita et al 2014 ). Several molecular targets were identified in the IL-6 pathway (CSNK2A1, MAPK3, IL6, JUN, STAT3, and FOS), but previous knockout studies failed to show that the IL-6 pathway was critical to rodent embryo development ( Sakurai et al 2012 , 2013 ; Yoshida et al 2011 ). In comparison, the finding of molecular targets in the MAPK pathway (MAPK3, IL1A, JUN, NFKB1, TGFB1, TNF, TP53, and FOS) is consistent with previous toxicity studies in Sertoli cells ( Qi et al 2014 ) and embryo limb bud cells ( Liu and Kapron 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Leung

Phuong

Baker

et al. 2016

Environ Health Perspect

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Background:Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.Objective:In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.Methods:We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.Results:A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.Conclusion:Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.Citation:Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050–1061; http://dx.doi.org/10.1289/ehp.1510385

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“…Intravenous (IV) injection of a high dose of a soluble antigen was shown to induce a state of long-lasting, antigen-specific immune tolerance (high-dose immune tolerance) (13). This approach has been successfully used to enable a safety study with an immunogenic mAb in mice (14). However, high-dose immune tolerance induction is not applicable for studies in which low-single dose is used or necessary dose levels cannot be reached.…”

Section: Introductionmentioning

confidence: 99%

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Piccand

Bessa

Schick

et al. 2015

AAPS J

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Abstract. The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age. After a single intravenous injection of the same mAb as used for tolerance induction, the pharmacokinetics of the mAb and formation of anti-drug antibodies (ADA) in plasma were assessed using ELISA. Tolerance induction to adalimumab was achieved in a maternal dose-dependent manner. Adalimumab immunetolerant offspring showed a slower adalimumab clearance (4.24±0.32 mL/day/kg) as compared to the control group (12.09±3.81 mL/day/kg). In the control group, accelerated clearance started 7 days after adalimumab dosing, whereas immune-tolerant offspring showed a log-linear terminal concentration-time course. In the offspring, the absence of predose ADA levels was indicative of successful tolerance induction. The second test compound efalizumab was not immunogenic in mice under our experimental conditions. Overall, the present study demonstrated the suitability of neonatal immune tolerance induction for a 4-week single dose study in adult mice with a human therapeutic mAb that is otherwise immunogenic in laboratory animals.

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The Effects of Interleukin‐6 Signal Blockade on Immune System, Reproductive and Skeletal Development in Juvenile Mice

Cited by 7 publications

References 75 publications

Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice

Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

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