Tocilizumab, a Humanized Anti-interleukin-6 Receptor Antibody, Ameliorates Joint Swelling in Established Monkey Collagen-Induced Arthritis

Uchiyama, Yasushi; Yorozu, Keigo; Hashizume, Misato; Moriya, Yoichiro; Mihara, Masahiko

doi:10.1248/bpb.31.1159

Cited by 47 publications

(45 citation statements)

References 19 publications

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“…61 In animal models of rheumatoid arthritis, anti-IL-6R antibodies reduced numbers of neutrophils and other cells of the myeloid lineage in inflamed joints. 62 Similarly, the humanized version of anti-IL-6R reduced cartilage turnover and decreased CRP levels in patients with juvenile rheumatoid arthritis 63 and in adults with active arthritis. 64 It is remarkable that elevated IL-6 occurring as a consequence of overexpression of TLR7 and the presence of the Sle1 locus sets off a sequelae of events that target developing progenitors, biasing their output away from lymphoid cell products to favor myeloid cell products.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

Maeda¹,

Malykhin²,

Teague-Weber

et al. 2009

Blood

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We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP ؊/؊ mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19 ؉ B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19 ؉ B-cell population and their progenitors recovered in an IL-6 ؊/؊ background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-␣ chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression. IntroductionAll hematopoietic cells develop from pluripotent hematopoietic stem cells (HSCs). Hematopoietic development proceeds in stages of decreasing lineage choices and decreasing capacity for selfrenewal of the progeny. HSCs feature a lack of all lineage markers (Lin Ϫ ) but express high levels of the receptor tyrosine kinase c-Kit (c-Kit hi ) and the surface protein Sca-1 (termed the LSK fraction). HSCs give rise to multipotent progenitors (MPPs), marked by a loss of self-renewal capacity, the ability to form either myeloid or lymphoid cells, and up-regulation of the Flk2/Flt3 receptor tyrosine kinase. 1 The earliest lymphoid-biased progenitors (ELPs) represent a subset of MPPs that can be resolved from all other progenitors on the basis of recombination activating gene 1 expression. 2 Lymphoid progenitors that develop from MPPs have reduced levels of c-Kit, display surface interleukin-7 receptor ␣ (IL-7R␣), and have other properties that define a population called common lymphoid progenitors (CLPs). 3 Hematopoiesis is normally a well-controlled system designed to replenish blood cells at a constant rate, such that the balance of lymphoid and myeloid cells is maintained. However, the rate of output of particular blood cell types can be altered by conditions such as leukemia, radiation, or acute inflammation. 4-11 One condition termed "emergency hematopoiesis," 12,13 is characterized by elevated production of myeloid cells, occurring during acute infections or acute allergic responses. The mechanism by which hematopoiesis is altered to elevate production of myeloid cells is not known. The consequence of emergency hematopoiesis is to increase circulating monocytes, granulocytes, and neutrophils, presumably present to fight infection.Interleukin-6 (IL-6) is a prominent cytokine produced during infectious disease (reviewed in...

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Section: Discussionmentioning

confidence: 99%

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

Maeda¹,

Malykhin²,

Teague-Weber

et al. 2009

Blood

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“…In contrast, tocilizumab targets include a wide spectrum of immune cells. Tocilizumab reduces the levels of circulating neutrophils, myeloid dendritic cells and monocytes [65,66] and the infiltration of neutrophils into inflamed joints of animal models of RA [67]. Tocilizumab also reduces the frequency of peripheral memory B cells and B cell hyper reactivity in RA patients [68], expands an intriguing B regulatory subset [69] and skews the balance between Th17 and Tregs towards a more protective status [70,71].…”

Section: Different Efficacy In Monotherapymentioning

confidence: 99%

“…Reduces neutrophil adhesion and chemotaxis [57] Decreases adhesion molecule expression Decreases levels of circulating neutrophils and the infiltration of neutrophils into inflamed joints [67] Dendritic cells Decreases the level of circulating dendritic cells and reduces the expression of activation markers [58] Reduces circulating myeloid dendritic cells [65] Monocyte-macrophage cells Inhibits macrophage activation [62] Decreases activating receptors for IgG on monocytes [63] Reduces the production of pro-inflammatory cytokines [59] and nitric oxide [61] Decreases levels of monocyte cells [65] Decreases serum macrophage migration inhibitory factor [66] T cells Reduces antigen-dependent T-cell proliferation [64] Decreases Th17 cells and increases Tregs cells [70][71] B cells Decreases antibody production by B cells [49] Reduces the development of anti-drug antibodies [56] Reduces the frequency of peripheral memory B cells and B cell hyperreactivity [68] Induces the expansion of B regulatory cells 69 …”

Section: Neutrophilsmentioning

confidence: 99%

Analysis of the Mechanism of Action of Biological Therapies in Monotherapy in Patients with Rheumatoid Arthritis: Beyond the ADACTA Study

Sanmarti¹

2013

Adv Pharmacoepidem Drug Safety

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The ADACTA study ADACTA is the first head-to-head study comparing two biological agents, tocilizumab and adalimumab on monotherapy. ADACTA was AbstractThe recently-published first head-to-head study comparing the efficacy of two biological drugs on monotherapy, tocilizumab and adalimumab, found better results for tocilizumab. Both are cytokine-specific antagonists: adalimumab targets tumor necrosis factor and tocilizumab targets interleukin-6 receptor.The aim of our review was to determine differences in the mechanisms of action of adalimumab and tocilizumab, in order to explain the differing results found, and to describe the immunologic and clinical aspects of the two drugs.

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“…Tocilizumab: amelioration of CiA in non-human primates Recent studies have been conducted in non-human primate models of CIA where relevant cellular immune mechanisms that are disrupted by blockade of the IL-6/IL6R/gp130 pathway with tocilizumab can be further explored. Uchiyama et al 76 showed that the development of CIA in female cynomolgus monkeys was suppressed after administration of tocilizumab 4 weeks after the onset of arthritis. The reduction in arthritis severity was accompanied by a significant decrease in joint swelling as well as in the level of neutrophils infiltrating the arthritic joints.…”

Section: Serum Amyloid Amentioning

confidence: 99%

Recent advances in neutralizing the IL-6 pathway in arthritis

Malemud

2009

OARRR

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Recent advances in understanding the mechanism(s) of how IL-6 trans-signaling regulates immune cell function and promotes inflammation in autoimmune arthritis are critically reviewed. Serum and/or synovial fluid (SF) IL-6 is markedly elevated in adult and juvenile rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and osteoarthritis (OA). IL-6, in concert with IL-17, determines the fate of CD4 + lymphocytes and therefore TH 17 cell differentiation. IL-6 also plays a critical role in modulating B-lymphocyte activity.The recognition that IL-6 trans-signaling regulates inflammation resulted in the development of tocilizumab, a fully humanized monoclonal antibody that neutralizes the biological activity of the IL-6-receptor (IL-6R). Significant clinical benefit was demonstrated as well as reduced serum IL-6 levels with suppression of X-ray progression of disease in several clinical trials in which juvenile or adult RA patients were treated with tocilizumab monotherapy or tocilizumab plus methotrexate. However, levels of serum and/or SF IL-6 cytokine protein superfamily members, adiponectin, oncostatin M, pre-B-cell colony enhancing factor/visfatin and leukemia inhibitory factor are also elevated in RA. Additional studies will be required to determine if anti-IL-6 trans-signaling inhibition strategies with tocilizumab or recombinant soluble IL-6R reduce the level of these cytokines.

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Tocilizumab, a Humanized Anti-interleukin-6 Receptor Antibody, Ameliorates Joint Swelling in Established Monkey Collagen-Induced Arthritis

Cited by 47 publications

References 19 publications

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

Analysis of the Mechanism of Action of Biological Therapies in Monotherapy in Patients with Rheumatoid Arthritis: Beyond the ADACTA Study

Recent advances in neutralizing the IL-6 pathway in arthritis

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