Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses

Hohki, Satoshi; Ohguro, Nobuyuki; Haruta, Hiroshi; Nakai, Kei; Terabe, Fumitaka; Serada, Satoshi; Fujimoto, Minoru; Nomura, Shosaku; Kawahata, Hirohisa; Kishimoto, Tadamitsu; Naka, Tetsuji

doi:10.1016/j.exer.2010.04.009

Cited by 80 publications

(46 citation statements)

References 42 publications

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“…Anti-IL-6R therapy is widely used to treat rheumatoid arthritis because of its strong anti-inflammatory effect [18,39,40]. Previous studies reported an effect of MR16-1 or tocilizumab on the Treg count [41,42], although other studies did not show any effect [43,44]. In our study, cytokine concentrations were not markedly increased in plasma from mSOD1 mice, except for CXCL1 (KC).…”

Section: Promising Effect Of Il-6 Blockade On Inflammation Statusmentioning

confidence: 41%

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

et al. 2016

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In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic impairment and neuroinflammation. Playing an important role in the regulation of both phenomena, interleukin (IL)-6, a major cytokine of the inflammatory response has been proposed as a target for management of ALS. Although a pilot clinical trial provided promising results in humans, another recent preclinical study showed that knocking out the IL-6 gene in mice carrying ALS did not improve clinical outcome. In this study, we aimed to determine the relevance of the IL-6 pathway blockade in a mouse model of ALS by using a pharmacological antagonist of IL-6, a murine surrogate of tocilizumab, namely MR16-1. We analyzed the immunological and metabolic effects of IL-6 blockade by cytokine measurement, blood cell immunophenotyping, targeted metabolomics, and transcriptomics. A deleterious clinical effect of MR16-1 was revealed, with a speeding up of weight loss (p = 0.0041) and decreasing body weight (p < 0.05). A significant increase in regulatory T-cell count (p = 0.0268) and a decrease in C-X-C ligand-1 concentrations in plasma (p = 0.0479) were observed. Metabolomic and transcriptomic analyses revealed that MR16-1 mainly affected branchedchain amino acid, lipid, arginine, and proline metabolism. IL-6 blockade negatively affected body weight, despite a moderated anti-inflammatory effect. Metabolic effects of IL-6 were mild compared with metabolic disturbances observed in ALS, but a modification of lipid metabolism by

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Section: Promising Effect Of Il-6 Blockade On Inflammation Statusmentioning

confidence: 41%

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

et al. 2016

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“…Dysregulation of IL-6 production leads to predominance of Th17 over Treg, but tocilizumab can repair this imbalance [Kimura and Kishimoto, 2010;Tanaka et al, 2011]. Indeed, in several animal disease models, anti-IL-6R antibody has been demonstrated to suppress antigen-specific Th17 and/or Th1 differentiation but induce antigen-specific Treg [Fujimoto et al, 2008;Serada et al, 2008;Yoshimura et al, 2009;Hohki et al, 2010;Haruta et al, 2011]. Alternatively, as described elsewhere, tocilizumab treatment can lead to a reduction of pathologic CD38 high CD19 low IgD negative plasma cells in SLE patients [Illei et al, 2010] and tocilizumab can diminish survival of the plasmablast population, which mainly produces AQP4 antibody in NMO [Chihara et al, 2011].…”

Section: Type II Diabetes Mellitusmentioning

confidence: 96%

Tocilizumab, a humanized anti‐interleukin‐6 receptor antibody, for the treatment of autoimmune disorders

Tanaka

Hagihara

Shima

et al. 2011

Drug Development Research

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The cytokine interleukin (IL)‐6 has a wide range of biological activities. It contributes to host defense against pathogens by inducing immune responses, hematopoiesis, and acute‐phase reactions. However, dysregulation of IL‐6 production plays a significant pathological role in various autoimmune and chronic inflammatory disorders. Because IL‐6 blockade was anticipated to provide a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti‐IL‐6 receptor antibody, was developed. Clinical trials have demonstrated the efficacy of tocilizumab for patients with moderate to severe rheumatoid arthritis, resulting in approval in more than 90 countries worldwide of this innovative biologic for the treatment of rheumatoid arthritis. Tocilizumab was also approved in Japan for the treatment of Castleman's disease and juvenile idiopathic arthritis. Results of recent pilot or case studies have indicated that tocilizumab may become a novel drug for various other autoimmune disorders, including systemic lupus erythematosus, systemic sclerosis, polymyositis, and vasculitis syndrome, as well as inflammatory disorders such as adult‐onset Still's disease, Crohn's disease, amyloid A amyloidosis, polymyalgia rheumatica, and spondylarthritides. It has been demonstrated that an imbalance of CD4‐positive T‐helper subsets [Th17 and/or Th1 >> regulatory T cells (Treg)] plays a major role in the development of several autoimmune disorders. In murine models of autoimmune disorders, the anti‐IL‐6 receptor antibody induced Treg and inhibited Th17 and/or Th1 differentiation, indicating that tocilizumab treatment may be able to repair this imbalance in human diseases as well. Drug Dev Res 72:717–732, 2011. © 2011 Wiley Periodicals, Inc.

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“…U očnoj vodici životinja sa eaU, nađene su povišene vrednosti il-6 (32), a njegov nivo je korelisao sa brojem limfocita i neutrofila (33). S druge strane, blokada il-6 smanjuje zapaljenje u eaU, moguće kroz inhibiciju Th17 odgovora (34). kod ljudi, il-6 se nalazi u povišenim koncentracijama u očnoj vodici osoba sa idiopatskim uveitisom (33).…”

Section: Interleukin-6 (Il-6)unclassified

Role of cytokines in the pathogenesis of endogenous uveitis

Stanković¹,

Vučević²,

Kovačević-Pavićević³

et al. 2012

Medicinski casopis

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UVODUveitisi su grupa zapaljenjskih bolesti očiju, koje primarno zahvataju uvealni trakt (dužicu, cilijarno telo i sudovnjaču), mada se termin uveitis nekad koristi i u širem smislu, za zapaljenja koja pored uvealnog trakta zahvataju i retinu i optički nerv (1). Uveitisi se najčešće javljaju kod radno sposobne populacije, uzrasta od 20 do 50 godina. ređe se javljaju kod dece, ali su kod njih u čak 75% slučajeva praćeni komplikacijama (2, 3). komplikacije uveitisa mogu trajno oštetiti vid, te stoga uveitisi imaju veliki socio-ekonomsko-medicinski značaj (4). naime, uveitisi su uzrok slepila kod 10% slepih širom sveta i nalaze se na četvrtom mestu svih uzročnika slepila (4, 5).Prema poreklu uveitisi se dele na egzogene i endogene. egzogeni uveitisi nastaju posle povrede oka ili hirurške intervencije na oku kada patogeni agensi, najčešće bakterije ili gljivice prodru u njega (4). endogeni uveitisi mogu da budu udruženi sa drugim bolestima kao što su sarkoidoza, multipla skleroza, Behčetova bolest, Vogtkojanagi-Harada sindrom i juvenilni idiopatski artritis. Opisana je i udruženost endogenih uveitisa sa infekcijama, moguće usled sličnosti (molekulske mimikrije) između pojedinih komponenti mikroorganizama i struktura uvealnog trakta. Pored toga, endogeni uveitisi mogu biti i idiopatski. U osnovi endogenih uveitisa leže imunski mehanizmi, pri čemu imunski odgovor mogu da pokrenu kako strani, tako i sopstveni antigeni (npr. S-antigen) koji interleukin-4, interleukin-5, interleukin-12, interleukin-17, interleukin-23, interferon-gamma and other

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Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses

Cited by 80 publications

References 42 publications

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

Tocilizumab, a humanized anti‐interleukin‐6 receptor antibody, for the treatment of autoimmune disorders

Role of cytokines in the pathogenesis of endogenous uveitis

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