Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy

Chan, Chang-Yien; Teo, Sharon; Lu, Liangjian; Chan, Yiong‐Huak; Lau, Philip; Than, Mya; Jordan, Stanley C.; Lam, Kong-Peng; Ng, Kar-Hui; Yap, Hui-Kim

doi:10.1016/j.trsl.2021.03.019

Cited by 8 publications

(7 citation statements)

References 52 publications

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“…At baseline, patients who relapsed following rituximab therapy showed significantly lower level of memory Tregs compared to those experience sustained remission. This finding confirms the results of a previous study in a pediatric cohort of patients with SDND and SRNS and biopsy-proven MCD on CNI-based immunosuppression [35]. In this study, lower Treg levels at baseline predicted the occurrence of early NS relapse post-rituximab with high sensitivity and specificity [35].…”

Section: Discussionsupporting

confidence: 91%

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome

Casiraghi

Todeschini

Podestà

et al. 2023

IJMS

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Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for adults. In these patients, treatment with rituximab allows safe discontinuation of steroids, but long-term efficacy is variable, and some patients experience NS relapses after B cell reconstitution. In this study, we aimed to determine disease-associated changes in the B and T cell phenotype of adult patients with SDND/FRNS after steroid-induced remission. We also investigated whether any of these changes in immune cell subsets could discriminate between patients who developed NS relapses after steroid-sparing treatment with rituximab from those who did not. Lymphocyte subsets in SDNS/FRNS patients (n = 18) were compared to those from patients with steroid-resistant NS (SRNS, n = 7) and healthy volunteers (HV, n = 15). Before rituximab, SDND/FRNS patients showed increased frequencies of total and memory B cells, mainly with a CD38-negative phenotype. Within the T-cell compartment, significantly lower levels of FOXP3+ regulatory T cells (Tregs) were found, mostly due to a reduction in CD45RO+ memory Tregs compared to both SRNS and HV. The levels of CD45RO+ Tregs were significantly lower at baseline in patients who relapsed after rituximab (n = 9) compared to patients who did not (n = 9). In conclusion, patients with SDND/FRNS displayed expansion of memory B cells and reduced memory Tregs. Treg levels at baseline may help identify patients who will achieve sustained remission following rituximab infusion from those who will experience NS relapses.

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Section: Discussionsupporting

confidence: 91%

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome

Casiraghi

Todeschini

Podestà

et al. 2023

IJMS

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“…For instance, earlier relapse was noted in children who had lower circulating regulatory T-cell and higher mitogenstimulated T-cell subsets before rituximab. 17,19 Repopulation of total memory B cells, and particularly of the switched memory B-cell subset, rather than total B cells, was also found to predict nephrotic syndrome relapse. 14,18,20 Immunophenotyping, especially at disease onset before immunosuppression, should be investigated for the discovery of biomarkers that aid individualized treatment strategies.…”

Section: Patient and Immunological Factors Determining Treatment Effi...mentioning

confidence: 96%

“…13 In addition, B-cell depletion can indirectly modulate the cross talk between B cells and specific T-cell subsets by affecting antigen presentation (MHC class II-TCR complex) and costimulation, resulting in a reduction of effector T cells such as Th2, Th17, T follicular helper (Tfh) cells, and invariant natural killer T (iNKT) cells and in a rise of regulatory T (Treg) cells. [14][15][16][17] Created with BioRender.com. The use of humanized anti-CD20 antibodies, such as ofatumumab, has been considered for the treatment of nephrotic syndrome in children with rituximab resistance, allergy, or development of anti-rituximab antibodies.…”

Section: Immunomodulatory Effects Of Rituximab Treatment In Childhood...mentioning

confidence: 99%

“…13 In addition, B-cell depletion can indirectly modulate the cross talk between B cells and specific T-cell subsets by affecting antigen presentation (MHC class II—TCR complex) and costimulation, resulting in a reduction of effector T cells such as Th2, Th17, T follicular helper (Tfh) cells, and invariant natural killer T (iNKT) cells and in a rise of regulatory T (Treg) cells. 14–17 Created with BioRender.com.…”

Section: Immunomodulatory Effects Of Rituximab Treatment In Childhood...mentioning

confidence: 99%

“…B-cell depletion could affect the production of the described nephrotic syndrome-associated podocyte-damaging autoantibodies such as anti-CD40, anti-UCHL1, and antinephrin IgG[10][11][12] or cytokines such as IL-4, produced by B cells activated locally in the glomerulus 13. In addition, B-cell depletion can indirectly modulate the cross talk between B cells and specific T-cell subsets by affecting antigen presentation (MHC class II-TCR complex) and costimulation, resulting in a reduction of effector T cells such as Th2, Th17, T follicular helper (Tfh) cells, and invariant natural killer T (iNKT) cells and in a rise of regulatory T (Treg) cells [14][15][16][17]. Created with BioRender.com.…”

mentioning

confidence: 99%

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Use of Rituximab in Childhood Idiopathic Nephrotic Syndrome

Chan

Yap

Colucci

et al. 2023

CJASN

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Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short to medium term disease remission and avoid steroid toxicities. Recent trials focus on its use as a first-line agent among those with milder disease severity. Rituximab is used in multi-drug refractory nephrotic syndrome and post-transplant disease recurrence, although the evidence is much less substantial. Available data suggest that the treatment response to rituximab depends on various patient factors, dosing regimen and the concomitant use of maintenance immunosuppression. Following repeated treatments, patients are found to have an improving response overall with longer relapse-free period. The drug effect, however, is not permanent and 80% of patients eventually relapse and many will require an additional course of rituximab. This underpins the importance to understand the long-term safety profile upon repeated treatments. Although rituximab appears to be generally safe, there are concerns of long-term hypogammaglobulinaemia, especially in young children. Reliable immunophenotyping and biomarkers are yet to be discovered to predict treatment success, risk of both rare and severe side-effects, persistent hypogammaglobulinaemia and to guide on re-dosing strategy. In this review, we highlight recent advances on the use of rituximab for childhood nephrotic syndrome and how the therapeutic landscape is evolving.

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The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature

et al. 2022

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Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy

Cited by 8 publications

References 52 publications

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome

Use of Rituximab in Childhood Idiopathic Nephrotic Syndrome

The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature

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