Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy

Anolik, Jennifer H.; Barnard, Jennifer; Owen, Teresa; Zheng, Bo; Kemshetti, Sunil; Looney, R. John; Sanz, Iñaki

doi:10.1002/art.22810

Cited by 273 publications

(260 citation statements)

References 41 publications

(37 reference statements)

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“…The study by Iwata and colleagues 2 confirms our finding that longterm remission in SLE patients treated with B cell depletion therapy is associated with a prolonged paucity of memory B cells and a reconstitution dominated by "naive" B cells 9,10 . Unfortunately, the limited B cell phenotyping in the present study does not distinguish naive from transitional B cells (transitional B cells would be embedded in the naive IgD+CD27-population).…”

Section: Rheumatologysupporting

confidence: 52%

Immunologic Reconstitution After Rituximab in Systemic Lupus Erythematosus: Why Should We Care?

Anolik¹

2011

J Rheumatol

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Section: Rheumatologysupporting

confidence: 52%

Immunologic Reconstitution After Rituximab in Systemic Lupus Erythematosus: Why Should We Care?

Anolik¹

2011

J Rheumatol

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“…Certainly, tissue B cell repopulation can occur prior to detectable return to the peripheral blood (20). Furthermore, variability in the phenotype of the repopulating B cells has been demonstrated following rituximab therapy in patients with systemic lupus erythematosus (40), and this may contribute to the variable duration of clinical effect.…”

Section: Discussionmentioning

confidence: 99%

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

Jones¹,

Ferraro²,

Chaudhry³

et al. 2009

Arthritis & Rheumatism

323

214

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Objective. B cell depletion with rituximab has allowed remissions in relapsing or refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in small studies. The aim of this study was to determine the efficacy and safety of rituximab for ANCA-associated vasculitis in a larger multicenter cohort. This permitted comparison of rituximab dosing regimens, the value of continuing immunosuppression, and investigation of ANCA and B cell levels as retreatment biomarkers.Methods. Retrospective, standardized data collection from 65 sequential patients receiving rituximab for refractory ANCA-associated vasculitis at 4 centers in the UK was used.Results. All patients achieved B cell depletion. Complete remission occurred in 49 of the 65 patients (75%), partial remission in 15 (23%), and no response in 1 (2%). The prednisolone dosage was reduced from 12.5 mg/day (median) to 9.0 mg/day at 6 months (P ‫؍‬ 0.0006). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). Twenty-eight of 49 patients who achieved full remission (57%) experienced relapse (median 11.5 months). B cell return preceded relapse in 14 of 27 patients (52%). Although ANCA levels fell after rituximab therapy, relapse was not associated with ANCA positivity or a rise in ANCA levels. Neither the initial rituximab regimen (4 infusions of 375 mg/m 2 each given 1 week apart or 2 infusions of 1 gm each given 2 weeks apart) nor withdrawal of immunosuppressive therapy (37 of 60 patients [62%]) influenced the timing of relapse. Thirty-eight patients received >2 courses of rituximab, and complete remission was induced or maintained in 32 of them (84%). IgM levels fell, although IgG levels remained stable. Forty-six serious adverse events occurred, including 2 episodes of lateonset neutropenia, which were attributed to rituximab.Conclusion. Rituximab was effective remission induction therapy for refractory ANCA-associated vasculitis in this study. There was no difference in efficacy between the 2 main treatment regimens. Continuing immunosuppression did not reduce relapses. Relapses occurred, but re-treatment was effective and safe. There was no clear influence of rituximab on the frequency of serious adverse events. ANCA and B cell levels lacked sufficient sensitivity to guide the timing of re-treatment.

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“…Rituximab is a pan-B humanized mAb (anti-CD20) that has been applied for total B-cell depletion in multiple autoimmune diseases. However, in spite of a certain beneficial effect in SLE patients, Rituximab cannot eliminate the CD20 À long-lived plasma cells [12][13][14][15].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, mAbs have been introduced into practice as a targeted therapeutic approach. B-cell depletion by means of anti-CD20 mAb [12][13][14][15], or inhibition of B-cell activation and proliferation by anti-CD22 mAb Epratuzumab have been applied to lupus patients [16]. The human Lymphostat-B mAb that blocks another important costimulatory receptor, B-cell activating factor (BAFF), has been also successfully introduced [17][18][19].…”

mentioning

confidence: 99%

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

Kerekov¹,

Mihaylova²,

Grozdev³

et al. 2011

Eur J Immunol

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Although the exact etiology of systemic lupus erythematosus (SLE) remains elusive, B-cell hyperactivity and production of autoantibodies directed to components of the cell nucleus are a well-established pathogenetic mechanism of the disease. Therefore, the targeted inhibition of DNA-specific B cells is a logical therapeutic approach. The complement receptor type 1 (CR1, CD35) has been shown to suppress human B-cell activation and proliferation after co-cross-linking with the BCR, and may serve as a mediator for negative signal delivery. In order to evaluate this therapeutic approach in a human-like system, we used immune-restricted SCID mice transferred with PBMCs from SLE patients. The tolerance of these humanized SCID mice to native DNA was re-established after administration of a chimeric molecule consisting of a CR1-specific mAb coupled to the decapeptide DWEYSVWLSN that mimics dsDNA. The generated protein-engineered chimera was able to co-cross-link selectively native DNA-specific BCR with the B-cell inhibitory receptor CR1, thus delivering a strong inhibitory signal.Key words: Chimeric molecules . Inhibitory B-cell receptors . SCID models of SLE IntroductionThe pathogenesis of systemic lupus erythematosus (SLE) is characterized by the formation of autoantibodies against a wide range of self-antigens. Development of this multi-system autoimmune syndrome in many severe cases leads to mortality. SLE patients develop high-titered anti-nuclear antibodies (ANA), the majority of them against double-stranded (ds) DNA. Multiple organs can be involved in human SLE (skin, lung, heart, arteries, nervous system), but kidneys being most severely affected. The pathological changes are provoked by deposition of immune complexes into renal glomeruli, followed by kidney structure damages and development of nephritis and proteinuria [1]. 3301The pathogenetic role of self-specific B cells has been attributed not only to the generation of autoreactive antibodies, but also to their antigen-presenting functions [2,3]. A number of studies have clearly documented the strong correlation between the level of these B cells and disease severity. The efficacy of B-cell depletion therapy further supports the key role of B cells in the pathology of SLE. Activity of any self-specific B cells is regulated by the interplay of multiple factors controlling B-cell proliferation and differentiation. BCR-mediated activation may be counteracted by a number of inhibitory receptors: CD32 (FcgRIIb), CD22, CD5, CD72, CD66a, ILT2, PIR-B, CD279 (PD-1), LAIR-1, as well as the complement receptor type 1 (CR1, CD35). While a reduced expression of these receptors can result in uncontrolled B-cell activation [4,5] and autoimmunity, their cross-linking inhibits B-cell activation and proliferation and may serve for targeted suppressive signal delivery [6,7].Non-specific immunosuppressive drugs are by now the most frequent therapy for autoimmune diseases, including SLE. Their effects are purely symptomatic while most of them are associated with severe side ef...

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Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy

Cited by 273 publications

References 41 publications

Immunologic Reconstitution After Rituximab in Systemic Lupus Erythematosus: Why Should We Care?

Immunologic Reconstitution After Rituximab in Systemic Lupus Erythematosus: Why Should We Care?

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

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