Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis

Sfikakis, Petros P.; Souliotis, Vassilis L.; Fragiadaki, Kalliopi; Moutsopoulos, H. M.; Boletis, John; Theofilopoulos, A. N.

doi:10.1016/j.clim.2006.12.006

Cited by 180 publications

(135 citation statements)

References 54 publications

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“…Ultimately, the reversible nature of the regulatory defect in these cells would allow the potential recovery of Treg cell function upon ex vivo culture with anti-DNA peptide. Consistent with this hypothesis, a recent study demonstrated that following B cell depletion in vivo, the expression of FoxP3 increased in all patients and this persisted only in patients with clinical remission, but it decreased in patients with active disease (44). While the results of that study reiterated the beneficial role of FoxP3ϩ cells in SLE, our results indicate a novel possibility for effectively modulating the number of FoxP3ϩ Treg cells in seropositive SLE patients.…”

Section: Discussionsupporting

confidence: 75%

Anti‐DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients

Hahn¹,

Anderson²,

Le³

et al. 2008

Arthritis & Rheumatism

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Section: Discussionsupporting

confidence: 75%

Anti‐DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients

Hahn¹,

Anderson²,

Le³

et al. 2008

Arthritis & Rheumatism

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“…The effects of rituximab extend beyond B cell depletion and may involve altering the phenotype and function of the remaining B cell subsets (18), normalization of T cell abnormalities (19), and promoting expansion of the regulatory T cell population (20,21). The possibility of T cell involvement in FSGS was suggested by an earlier study on renal biopsy tissue, where IL-2 receptora mRNA transcripts were detected in 14 of 20 patients with FSGS (22).…”

Section: Introductionmentioning

confidence: 92%

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Chan

Liu

Resontoc

et al. 2016

CJASN

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Background and objectives Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified.Design, setting, participants, & measurements Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m 2 ) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab.Results Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154 + CD4 + CD3 + subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%628.1% versus 78.9%616.4%; P=0.03). IFN-g + CD3 + and IL-2 + CD3 + were similarly decreased in responders compared with nonresponders (0.6%60.8% versus 7.5%66.1%; P=0.003 and 0.2%60.5% versus 4.0%64.7%; P,0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154 + CD4 + CD3 + , 74.8%617.2%; IFN-g + CD3 + , 7.1%67.7%; and IL-2 + CD3 + , 7.9%610.9%; P,0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154 + CD4 + CD3 + ,83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-g + CD3 + ,2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2 + CD3 + ,0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response.Conclusions We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.

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“…Also, B cell expansion blocks T cell regulatory activity, suggesting that depletion of B cells could expand a regulatory T cell population (47). Expansion of regulatory T cells has also recently been observed in lupus nephritis patients treated with rituxmab (48).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4+ T Cell Reactivity

Hamel¹,

Doodes²,

Cao

et al. 2008

The Journal of Immunology

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B cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) since the discovery of RA as an autoimmune disease. There is renewed interest in B cells in RA based on the clinical efficacy of B cell depletion therapy in RA patients. Although, reduced titers of rheumatoid factor and anti-cyclic citrullinated peptide Abs are recorded, the mechanisms that convey clinical improvement are incompletely understood. In the proteoglycan-induced arthritis (PGIA) mouse model of RA, we reported that Ag-specific B cells have two important functions in the development of arthritis. PG-specific B cells are required as autoantibody-producing cells as well as Ag-specific APCs. Herein we report on the effects of anti-CD20 mAb B cell depletion therapy in PGIA. Mice were sensitized to PG and treated with anti-CD20 Ab at a time when PG-specific autoantibodies and T cell activation were evident but before acute arthritis. In mice treated with anti-CD20 mAb, development of arthritis was significantly reduced in comparison to control mAb-treated mice. B cell depletion reduced the PG-specific autoantibody response. Furthermore, there was a significant reduction in the PG-specific CD4+ T cell recall response as well as significantly fewer PG-specific CD4+ T cells producing IFN-γ and IL-17, but not IL-4. The reduction in PG-specific T cells was confirmed by the inability of CD4+ T cells from B cell-depleted mice to adoptively transfer disease into SCID mice. Overall, B cell depletion during PGIA significantly reduced disease and inhibited both autoreactive B cell and T cell function.

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Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis

Cited by 180 publications

References 54 publications

Anti‐DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients

Anti‐DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4+ T Cell Reactivity

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