Anti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases

Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

doi:10.1016/j.febslet.2011.03.023

Cited by 129 publications

(102 citation statements)

References 159 publications

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“…Therefore, in AE, fewer cycles of tocilizumab might substantively Data are reported as median (interquartile range) unless otherwise indicated *Corresponds to mRS at the time of tocilizumab initiation in the tocilizumab group, at initiation of additional rituximab for additional rituximab group, and at 1 month from the last rituximab therapy for observation group, respectively mRS: modified Rankin Scale, IQR: interquartile range, † p < 0.05 for tocilizumab group vs observation group ‡ p < 0.05 for additional rituximab group vs observation group § p < 0.05 for tocilizumab group vs additional rituximab group improve the long-term outcomes, and the clinical response to tocilizumab treatment can be detected at early phase and be maintained throughout long-term follow-up. We found that the frequency of infectious or infusionrelated complications of tocilizumab were low, which is comparable with a previous report [12]. However, 3 patients had a moderately severe reduction in absolute neutrophil count.…”

Section: Discussionsupporting

confidence: 79%

“…IL-6 inhibits regulatory T-cell differentiation, which is crucial in maintaining the balance against IL-17-producing T-helper cells in regulating autoimmune processes [14]. Furthermore, IL-6 stimulates the differentiation of CD8 + cytotoxic T cells, which promote excitotoxicity-induced neuronal damage [12,13]. Considering that rituximab does not affect cytokines or antibody-producing plasma cells, we suggest that tocilizumab could potentially represent a good strategy for AE with inadequate response to rituximab, by blocking IL-6 and thereby ameliorating autoimmune neuronal damage with multidirectional mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 not only induces B-cell differentiation and proliferation [12,15], but also promotes the differentiation of a main inducer of autoimmune tissue damage, IL-17-producing T-helper cells, from naive T cells [32]. IL-6 inhibits regulatory T-cell differentiation, which is crucial in maintaining the balance against IL-17-producing T-helper cells in regulating autoimmune processes [14].…”

Section: Discussionmentioning

confidence: 99%

“…Tocilizumab is a humanized anti-interleukin (IL)-6 receptor monoclonal antibody, which blocks IL-6-mediated signal transduction [12]. Owing to the crucial role of IL-6 in stimulating both B and T cells in autoimmune processes [13][14][15], tocilizumab was established as efficient in various autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus [16][17][18].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

et al. 2016

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A considerable portion of autoimmune encephalitis (AE) does not respond to conventional immunotherapies and subsequently has poor outcomes. We aimed to determine the efficacy of tocilizumab, an anti-interleukin-6 antibody, in rituximab-refractory AE compared with other treatment options. From an institutional cohort of AE, 91 patients with inadequate clinical response to first-line immunotherapy and following rituximab were retrospectively reviewed. Patients were grouped according to their further immunotherapy strategies. Thirty (33.0 %) patients were included in the tocilizumab group, 31 (34.0 %) in the additional rituximab group, and 30 (33.0 %) in the observation group. Outcomes were defined as the favorable modified Rankin Scale scores (≤2) at 1 and 2 months from the initiation of each treatment strategy and at the last follow-up. Favorable clinical response (improvement of the modified Rankin Scale scores by ≥ 2 points or achievement of the mRS scores ≤ 2) at the last follow-up was also analyzed. The tocilizumab group showed more frequent favorable mRS scores at 2 months from treatment initiation and at the last follow-up compared with those at the relevant time points of the remaining groups. The majority (89.5 %) of the patients with clinical improvement at 1 month from tocilizumab treatment maintained a long-term favorable clinical response. No serious adverse effects of rituximab or tocilizumab were reported. Therefore, we suggest that tocilizumab might be a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab. The tocilizumab-mediated clinical improvement manifests as early at 1 month after treatment initiation.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

et al. 2016

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“…The mAb tocilizumab, which is directed against the human IL-6R, is successfully used to treat rheumatoid arthritis and Still's disease. [16][17][18] However, some significant caveats remain. Besides its proinflammatory role, IL-6 signaling has also been shown to exert strong anti-inflammatory effects.…”

mentioning

confidence: 99%

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

Luig¹,

Kluger²,

Goerke³

et al. 2015

Journal of the American Society of Nephrology

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IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Ra, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6 2/2 mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.

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Immunological Tolerance: Therapeutic Induction

Mair¹,

Reynolds²,

Anderton³

2013

Encyclopedia of Life Sciences

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When the natural mechanisms of immune tolerance break down, autoimmune or allergic disease can result. There is considerable experimental evidence that the ultimate response to antigen, full immunity or tolerance, is dependent on the activation status of the antigen‐presenting dendritic cells, with those in steady state inducing tolerance. Current therapeutic options either deplete immune cell populations, interfere with immune cell trafficking to the tissues or inhibit inflammatory cytokine function or lymphocyte signalling. Although these treatments can be effective for certain diseases, they carry with them significant adverse effects and it is unlikely that they induce true, long‐lived immune tolerance. Cellular therapies using either tolerogenic dendritic cells or regulatory T cells may be able to achieve this. Alternatively, administration of antigen in tolerogenic form can provide the most specific therapy, with the least risk of adversely affecting normal immune function against infection or neoplasia. Key Concepts: Peripheral tolerance mechanisms consist of lymphocyte apoptosis, anergy and regulation. Current therapeutic options for the clinic can be effective, but in general are nonspecific and may not provide long‐term tolerance. Dendritic cell (DC) activation status determines the type of immune response. Activated DC provokes immunity whereas steady‐state DC promotes tolerance. ‘Tolerogenic’ DC can be administered to give protection from autoimmune disease, allergy and graft rejection as shown in animal models, and are being tested for clinical application. Administration of antigen in tolerogenic form (without adjuvant) also provides protection from disease in animal models; however, clinical translation is proving challenging. Transfer of antigen‐specific regulatory T cells (Treg) can also protect against disease, and can be curative in some models. Translation of cellular therapies (using DC or Treg) or tolerogenic antigen will require a fuller understanding of the critical autoantigens/epitopes that drive autoimmune pathology.

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Anti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases

Cited by 129 publications

References 159 publications

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

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

Immunological Tolerance: Therapeutic Induction

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