Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients

Pesce, Bárbara; Soto, Lilian; Sabugo, Francisca; Wurmann, Pamela; Cuchacovich, Miguel; López, Mercedes; Sotelo, Pablo H.; Molina, Marı́a; Aguillón, Juan Carlos; Catalán, Diego

doi:10.1111/cei.12017

Cited by 110 publications

(76 citation statements)

References 22 publications

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“…In the case of RA, it has been shown that tocilizumab treatment led to improvement in systemic and joint inflammatory markers (Garnero et al 2010;Terpos et al 2011;Kanbe et al 2012), but it remained to be determined whether it can rectify fundamental immunological abnormalities, such as autoantibody production or imbalance of effector CD4 þ T-cell subsets (Tanaka 2013). However, recent preliminary results indicate that tocilizumab treatment can correct the imbalance between Th17 and Treg in peripheral blood CD4 þ T cells (Samson et al 2012;Pesce et al 2013). Moreover, it was shown that the treatment caused a reduction in the level of serum IgG4-class anticyclic citrullinated peptide Ab in RA (Carbone et al 2013).…”

Section: Il-6 In Inflammation Immunity and Diseasementioning

confidence: 99%

IL-6 in Inflammation, Immunity, and Disease

Tanaka

Narazaki

Kishimoto

2014

Cold Spring Harbor Perspectives in Biology

3,556

2,426

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Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.

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Section: Il-6 In Inflammation Immunity and Diseasementioning

confidence: 99%

IL-6 in Inflammation, Immunity, and Disease

Tanaka

Narazaki

Kishimoto

2014

Cold Spring Harbor Perspectives in Biology

3,556

2,426

View full text Add to dashboard Cite

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“…1) [1,19]. Through this mechanism, TCZ decreases the circulating levels of neutrophils, neutrophil infiltration into inflamed joints [20], circulation of myeloid dendritic cells [21], monocyte levels, serum macrophage migration inhibitory factor levels [21,22], and levels of T helper 17 (Th17) cells, while increasing regulatory T cells [23,24]. TCZ also induces regulatory B-cell expansion, decreases B-cell hyperactivity, and decreases the number of peripheral memory B cells.…”

Section: Tocilizumab: the First Interleukin-6 Receptor-neutralizing Bmentioning

confidence: 99%

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

et al. 2018

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Tocilizumab (TCZ) is the first humanized antiinterleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the longterm efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although longterm data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents. Keywords: Interleukin-6; Rheumatoid arthritis; Tocilizumab TOCILIZUMAB: THE FIRST INTERLEUKIN-6 RECEPTOR-NEUTRALIZING BIOLOGICInterleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in both acute and chronic inflammatory responses. Consequently, the dysregulated or persistent production of IL-6 can lead to the development of inflammatory disorders [1]. Elevated levels of IL-6 in serum, synovial fluid, and various tissues have been correlated with disease activity in patients with rheumatoid arthritis (RA) [2], juvenile idiopathic arthritis (JIA) [3,4], Castleman's disease [5,6], systemic sclerosis (SSc) [7], giant cell arteritis (GCA) [8,9], adult-onset Still's disease (AOSD) [10], familial Mediterranean fever (FMF) [11,12], Schnitzler's syndrome [13,14], polychondritis [15], and amyloidosis [1]. These associations suggest a pathogenetic role for IL-6 in multiple inflammatory conditions and form the basis of the rationale for the development of anti-IL-6 therapies.Tocilizumab (TCZ) is the first humanized monoclonal antibody targeting the IL-6 receptor subunit alpha (IL-6Ra) [16], and its mechanism of action has been described in detail in previous reviews [17,18]. Briefly, TCZ targets both membrane-bound and soluble IL-6Ra, which prevents t...

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“…B. Pesce и соавт. [108] также вы-явили увеличение числа Т рег после 4 и 6 мес терапии ТЦЗ в группе из 8 пациентов с активным РА, но не отметили влияния препарата на содержание Th17-лимфоцитов. J. Kikuchi и соавт.…”

Section: ингибиторы рецепторов интерлейкинаunclassified