Regulatory T-cell dynamics with abatacept treatment in rheumatoid arthritis

Langdon, Kane; Haleagrahara, Nagaraja

doi:10.1080/08830185.2018.1465943

Cited by 25 publications

(19 citation statements)

References 56 publications

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“…Furthermore, the development of GCs, autoantibodies, and autoimmune disease was not dependent upon prolonged circulation of CTLA4-Ig, which lasted 10-14 d. When young BXD2 mice were administered Ad-CTLA4-Ig at 2 mo of age, before significant autoantibodies and autoimmune disease was apparent, they remained autoantibody and disease free for up to 8 mo of age. These results are consistent with several reports that CTLA4-Ig promotes the function of Treg cells in patients with RA (148,149). It also has been reported that CTLA4-Ig may enhance IL-10 production by Treg cells and 1,25(OH)2D3 promotes the efficacy of CD28 costimulation blockade by abatacept (150).…”

Section: Therapeutic Directionssupporting

confidence: 92%

Dysregulation of T Follicular Helper Cells in Lupus

Mountz

Hsu

Ballesteros-Tato

2019

The Journal of Immunology

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Although multiple and overlapping mechanisms are ultimately responsible for the immunopathology observed in patients with systemic lupus erythematosus, autoreactive Abs secreted by autoreactive plasma cells (PCs) are considered to play a critical role in disease progression and immunopathology. Given that PCs derive from the germinal centers (GC), long-term dysregulated GC reactions are often associated with the development of spontaneous autoantibody responses and immunopathology in systemic lupus erythematosus patients. In this review, we summarize the emerging evidence concerning the roles of T follicular helper cells in regulating pathogenic GC and autoreactive PC responses in lupus.

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Section: Therapeutic Directionssupporting

confidence: 92%

Dysregulation of T Follicular Helper Cells in Lupus

Mountz

Hsu

Ballesteros-Tato

2019

The Journal of Immunology

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“…All 3 cases occurred early in the disease (11–46 days after randomization), while the 1 case in the placebo group occurred 56 days after randomization. Inhibition of Treg cell function prior to reduction in the numbers and activity of pathogenic effector T cells in abatacept‐treated patients could account for early flares but could also lead to eventual reduction in disease activity in SSc , though data are needed to validate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator‐Initiated, Multicenter, Double‐Blind, Randomized, Placebo‐Controlled Trial

Khanna

Spino

Johnson

et al. 2019

Arthritis & Rheumatology

194

141

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Objective T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods In this 12‐month, randomized, double‐blind, placebo‐controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. Results Among 88 participants, the adjusted mean change in the MRSS at 12 months was −6.24 units for those receiving abatacept and −4.49 units for those receiving placebo, with an adjusted mean treatment difference of −1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal‐like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. Conclusion In this phase II trial, abatacept was well‐tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

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“…Though our knowledge on the mechanisms of this fusion protein is still incomplete, current literature suggest that by interacting with B7 molecules on antigen-presenting cells, abatacept interferes with CD28-mediated T-cell signalling and activation [22]. Abatacept might also affect the activation of innate cells, such as monocytes and dendritic cells, and enhance Tregs, though data on the Treg function are limited and conflicting [23,24].…”

Section: @Erspublicationsmentioning

confidence: 99%

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

et al. 2020

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, inflammation-mediated severe lung damage and defective haemostasis are the main underlying reasons for morbidity and mortality in coronavirus disease 2019 (COVID-19) patients [1]. Several immunotherapies that target various inflammatory processes have been successfully used in COVID-19 patients and many other strategies are under evaluation [2, 3]. However, in view of dysregulated immune responses in severe COVID-19 patients, we suggest that CD4 + CD25 + FoxP3 + regulatory T-cell (Treg)-based strategies could be considered for patient management. Vigorous antimicrobial responses triggered against the pathogen can be detrimental to the host due to collateral tissue damage. Therefore, regulatory mechanisms, and in particular Tregs, are in place to ensure that inflammation is kept in check. Tregs are either thymus-derived or induced in the periphery and are classically known for stimulating immune tolerance, and preventing autoimmune and inflammatory diseases [4]. Tregs inhibit the activation of both innate and adaptive immune cells via inhibitory surface molecules (like cytotoxic T-lymphocyte antigen-4 (CTLA-4) and lymphocyte-activation gene-3) and secretion of immunosuppressive cytokines (interleukin (IL)-10, transforming growth factor-β and IL-35). Both Treg subsets are equally important to prevent inflammation-induced tissue damage during acute infections and to promote tissue repair, which is particularly shown in the influenza infection model [4, 5].

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Regulatory T-cell dynamics with abatacept treatment in rheumatoid arthritis

Cited by 25 publications

References 56 publications

Dysregulation of T Follicular Helper Cells in Lupus

Dysregulation of T Follicular Helper Cells in Lupus

Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator‐Initiated, Multicenter, Double‐Blind, Randomized, Placebo‐Controlled Trial

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

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