Rituximab in Minimal Change Disease

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Abstract

Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD). MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.

Abrégé

Le traitement par le rituximab, un anticorps monoclonal contre la protéine de surface CD20 des lymphocytes B, mène à l’appauvrissement de ces derniers. Le rituximab a récemment été signalé comme étant efficace pour prévenir les rechutes des maladies à changements minimes (MCD) dépendantes des glucocorticoïdes ou des MCD à rechutes fréquentes. On pense que les MCD pourraient être induites par les lymphocytes T, mais la manière dont le rituximab agit sur les MCD n’est pas encore bien comprise. Dans cette revue, nous résumons les principales études cliniques démontrant l’efficacité du rituximab dans le syndrome néphrotique idiopathique, principalement dans les MCD. Nous discutons ensuite des caractéristiques immunologiques de la maladie et des mécanismes d’action potentiels du rituximab dans son traitement, en nous basant sur ce que l’on connaît de l’action thérapeutique du rituximab dans d’autres troubles immunitaires. Nous sommes d’avis que des études visant une meilleure compréhension des mécanismes d’action du rituximab dans les MCD pourront fournir de nouvelles approches pour remédier à la pathophysiologie immunitaire des MCD.

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Most cited references 142

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Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.

Kevan C. Herold, William Hagopian, Julie A Auger … (2002)

Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease. We studied the effects of a nonactivating humanized monoclonal antibody against CD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease. Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment. Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.

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Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?

Anthony Smith, Amit Bar-Or, Taissa S Hauser … (2010)

To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS). B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS. B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-alpha secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFalpha. We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.

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Effector and regulatory B cells: modulators of CD4+ T cell immunity.

Frances E Lund, Troy D. Randall (2010)

B cells are essential for humoral immunity, but the role that they have in regulating CD4(+) T cell responses remains controversial. However, new data showing that the transient depletion of B cells potently influences the induction, maintenance and reactivation of CD4(+) T cells, with the recent identification of antibody-independent functions of B cells, have reinvigorated interest in the many roles of B cells in both infectious and autoimmune diseases. In this Review, we discuss recent data showing how effector and regulatory B cells modulate CD4(+) T cell responses to pathogens and autoantigens.

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Author and article information

Journal

Journal ID (nlm-ta): Can J Kidney Health Dis

Journal ID (iso-abbrev): Can J Kidney Health Dis

Journal ID (publisher-id): CJK

Journal ID (hwp): spcjk

Title: Canadian Journal of Kidney Health and Disease

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Electronic): 2054-3581

Publication date (Electronic): 13 March 2017

Publication date Collection: 2017

Volume: 4

Electronic Location Identifier: 2054358117698667

Affiliations

[1 ]Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada

[2 ]Division of Nephrology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada

Author notes

[*]Tomoko Takano, Division of Nephrology, Department of Medicine, McGill University Health Centre, 1001 Boulevard Décarie, EM1.3244, Montreal, Quebec, Canada H4A 3J1. Email: tomoko.takano@ 123456mcgill.ca

Article

Publisher ID: 10.1177_2054358117698667

DOI: 10.1177/2054358117698667

PMC ID: 5433659

PubMed ID: 28540057

SO-VID: d2ef3b09-6756-490c-bf5c-b18338a90c2a

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 23 September 2016

Date accepted : 23 November 2016

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cover-date January-December 2017

Keywords: minimal change disease,rituximab,nephrotic syndrome,steroid (glucocorticoid)-dependent nephrotic syndrome,frequently relapsing nephrotic syndrome,b cells,t cells

Data availability:

Keywords: minimal change disease, rituximab, nephrotic syndrome, steroid (glucocorticoid)-dependent nephrotic syndrome, frequently relapsing nephrotic syndrome, b cells, t cells

Rituximab in Minimal Change Disease : Mechanisms of Action and Hypotheses for Future Studies

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Gamma Delta T cells

Most cited references 142

Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.

Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?

Effector and regulatory B cells: modulators of CD4+ T cell immunity.

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