The Experts below are selected from a list of 198 Experts worldwide ranked by ideXlab platform
Dominique Baeten - One of the best experts on this subject based on the ideXlab platform.
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A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells
Journal of Autoimmunity, 2016Co-Authors: Charlotte Hua, Michael Hahne, Rachel Audo, Nataliya Yeremenko, Dominique Baeten, Bernard Combe, Jacques Morel, Claire DaienAbstract:B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B-cell functions are impaired in patients with rheumatoid arthritis (RA) and that mice transgenic for a proliferation-inducing ligand (APRIL) are protected against collagen-induced arthritis. We aimed to explore the effect of APRIL on human B-cell IL-10 production, in healthy subjects and in patients with RA. The IL-10 production of B-cell was greater with APRIL than with BLyS or control medium, in a dose dependent manner. TACI expression was greater in IL-10 producing B cells (B10) than non-IL-10-producing B cells whereas BAFF-R expression was lower. TNF-α and IFN-γ secretion of T-cells were decreased by APRIL-stimulated B cells. APRIL stimulated STAT3 and STAT3 inhibition decreased B10 cells. APRIL also promoted B10 cells in RA patients. In conclusion, APRIL but not BLyS promotes IL-10 production by CpG-activated B cells and enhances the regulatory role of B cells on T cells. B10 cells in RA patients are responsive to APRIL, which suggests a possible therapeutic application of APRIL to expand B10 cells. This could also explain the difference of clinical efficacy observed between belimumab and Atacicept in RA.
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The TNF family member APRIL dampens collagen-induced arthritis
Annals of the Rheumatic Diseases, 2013Co-Authors: Leticia Fernandez, Nataliya Yeremenko, Bernard Combe, Jacques Morel, Gabriela Franco Salinas, Cecilia Rocha, Carla Carvalho-pinto, Laura Papon, Jan Paul Medema, Dominique BaetenAbstract:BACKGROUND: The tumour necrosis factor (TNF)-family members B cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) play important roles in B cell biology, and share binding to B cell maturation antigen and transmembrane activator and cyclophilin ligand interactor, both receptors of the TNF-family. However, while it is reported that BAFF can break B cell tolerance, the role of APRIL in autoimmunity remains elusive. OBJECTIVE: To evaluate the role of APRIL on collagen-induced arthritis (CIA). METHODS: CIA was induced in APRIL-transgenic (Tg) DBA/1 mice and littermates. Disease progression was evaluated by clinical and histological signs of arthritis. In another experimental setting mice were exposed to the collagen antibody-induced arthritis. In addition, we tested T cell dependent humoral responses in APRIL-Tg mice. RESULTS: We found that APRIL-Tg displayed a strongly reduced incidence and severity of CIA compared with littermates, with decreases in collagen-specific autoantibody titres, immune complex deposition and downstream mast cell activation in joints. Notably, ectopic APRIL-expression was also found to negatively regulate T cell dependent humoral responses. The lower autoantibody production in APRIL-Tg mice during CIA appears to be crucial, as arthritis induced by administration of anti-collagen antibodies developed similar in APRIL-Tg and control mice, thus demonstrating that the downstream effector pathways induced by anti-collagen antibodies remain intact in APRIL-Tg mice. This protective effect was specifically mediated by APRIL, as adenoviral delivery of APRIL decreased CIA in a therapeutic setting. CONCLUSIONS: Collectively, our data identify APRIL as a negative regulator of CIA by regulating autoantibody production. These findings are of important clinical relevance, as the therapeutic potential of transmembrane activator and cyclophilin ligand interactor-Fc (Atacicept) is presently evaluated in clinical trials.
Mark C Genovese - One of the best experts on this subject based on the ideXlab platform.
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Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy results of a phase ii randomized placebo controlled dose finding trial
Arthritis & Rheumatism, 2011Co-Authors: Mark C Genovese, N Kinnman, G De La Bourdonnaye, Pena C Rossi, Paul P TakAbstract:Objective To assess the efficacy, safety, and biologic activity of Atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate. Methods The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive Atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level. Results No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, Atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti–citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with Atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment. Conclusion This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of Atacicept was considered acceptable in this patient population.
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reduced b lymphocyte and immunoglobulin levels after Atacicept treatment in patients with systemic lupus erythematosus results of a multicenter phase ib double blind placebo controlled dose escalating trial
Arthritis & Rheumatism, 2007Co-Authors: Maria Dallera, Mark C Genovese, Eliza F Chakravarty, Daniel J Wallace, Michael H Weisman, Arthur Kavanaugh, Kenneth C Kalunian, Patricia Dhar, Emmanuelle Vincent, Claudia PenarossiAbstract:Objective To assess the safety and tolerability of Atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of Atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI-Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation-inducing ligand. Methods This phase Ib, double-blind, placebo-controlled, dose-escalating trial comprised 6 cohorts of patients treated with Atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1–4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of Atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of Atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1–4) or 9 weeks (cohorts 5 and 6). Patients with mild-to-moderate SLE were enrolled. Results Biologic activity of Atacicept was demonstrated by dose-dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated-dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection-site reactions occurred more frequently among the Atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with Atacicept. Conclusion Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.
Nora G Singer - One of the best experts on this subject based on the ideXlab platform.
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Atacicept in combination with mmf and corticosteroids in lupus nephritis results of a prematurely terminated trial
Arthritis Research & Therapy, 2012Co-Authors: Ellen M Ginzler, Stephen Wax, Anand Rajeswaran, Samuel Copt, Jan Hillson, Eleanor L Ramos, Nora G SingerAbstract:Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN study aimed to evaluate the efficacy and safety of Atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF). This was a randomized, double-blind, placebo-controlled Phase II/III, 52-week study. At screening (Day -14), patients initiated high-dose CS (the lesser of 0.8 mg/kg/day or 60 mg/day prednisone) and MMF (1 g daily, increased by 1 g/day each week to 3 g daily). From Day 1, Atacicept (150 mg, subcutaneously, twice weekly for 4 weeks, then weekly) was initiated with MMF along with a tapered dose of CS. The trial was terminated after the enrollment of six patients, due to an unexpected decline in serum immunoglobulin G (IgG) and the occurrence of serious infections. Efficacy was thus not evaluated. By Day 1, serum IgG levels had declined substantially in patients then randomized to Atacicept (n = 4) compared with placebo (n = 2). Patients receiving Atacicept also had more severe proteinuria on Day -14 than those on placebo. Lymphocyte counts were low at screening in all patients. IgG decline continued following initiation (Day 1) of Atacicept. Three Atacicept-treated patients developed serum IgG below the protocol-defined discontinuation threshold of 3 g/l, two of whom developed serious pneumonia. Future studies are needed to characterize the safety, efficacy, and pharmacodynamic response of Atacicept in LN patients. ClinicalTrials.gov: NCT00573157
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Atacicept in combination with mmf and corticosteroids in lupus nephritis results of a prematurely terminated trial
Arthritis Research & Therapy, 2012Co-Authors: Ellen M Ginzler, Stephen Wax, Anand Rajeswaran, Samuel Copt, Jan Hillson, Eleanor L Ramos, Nora G SingerAbstract:Introduction: Atacicept is a soluble, fully human, recombinant fusion protein that inhibits B cell-stimulating factors APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator). The APRIL- LN study aimed to evaluate the efficacy and safety of Atacicept in patients with active lupus nephritis (LN), receiving newly initiated corticosteroids (CS) and mycophenolate mofetil (MMF). Methods: This was a randomized, double-blind, placebo-controlled Phase II/III, 52-week study. At screening (Day -14), patients initiated high-dose CS (the lesser of 0.8 mg/kg/day or 60 mg/day prednisone) and MMF (1 g daily, increased by 1 g/day each week to 3 g daily). From Day 1, Atacicept (150 mg, subcutaneously, twice weekly for 4 weeks, then weekly) was initiated with MMF along with a tapered dose of CS. Results: The trial was terminated after the enrollment of six patients, due to an unexpected decline in serum immunoglobulin G (IgG) and the occurrence of serious infections. Efficacy was thus not evaluated. By Day 1, serum IgG levels had declined substantially in patients then randomized to Atacicept (n = 4) compared with placebo (n = 2). Patients receiving Atacicept also had more severe proteinuria on Day -14 than those on placebo. Lymphocyte counts were low at screening in all patients. IgG decline continued following initiation (Day 1) of Atacicept. Three Atacicept-treated patients developed serum IgG below the protocol-defined discontinuation threshold of 3 g/l, two of whom developed serious pneumonia. Conclusions: Future studies are needed to characterize the safety, efficacy, and pharmacodynamic response of Atacicept in LN patients. Trial Registration: ClinicalTrials.gov: NCT00573157
Pascal Schneider - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Membrane-Bound BAFF by the Anti-BAFF Antibody Belimumab
Frontiers in immunology, 2018Co-Authors: Christine Kowalczyk-quintas, Laure Willen, Dehlia Chevalley, Camilla Jandus, Michele Vigolo, Pascal SchneiderAbstract:B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control Atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than Atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as Atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF in vitro. In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin.
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Table_1_Inhibition of Membrane-Bound BAFF by the Anti-BAFF Antibody Belimumab.PDF
2018Co-Authors: Christine Kowalczyk-quintas, Laure Willen, Dehlia Chevalley, Camilla Jandus, Michele Vigolo, Pascal SchneiderAbstract:B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control Atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than Atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as Atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF in vitro. In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin.
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Data_Sheet_1_Inhibition of Membrane-Bound BAFF by the Anti-BAFF Antibody Belimumab.pdf
2018Co-Authors: Christine Kowalczyk-quintas, Laure Willen, Dehlia Chevalley, Camilla Jandus, Michele Vigolo, Pascal SchneiderAbstract:B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control Atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than Atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as Atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF in vitro. In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin.
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Gel filtration analysis of BAFFR-Fc, TACI-Fc, Fn14-Fc and Atacicept.
2013Co-Authors: Josquin Nys, Cristian R. Smulski, Aubry Tardivel, Laure Willen, Christine Kowalczyk, Olivier Donzé, Bertrand Huard, Henry Hess, Pascal SchneiderAbstract:Panel A. Superdex-200 elution profiles of the indicated receptors-Fc monitored at 280 nm. The elution position of molecular mass standards is indicated at the top of the profiles. Panel B. BMDMs were treated with TACI-Fc obtained before (total preparation) or after size exclusion chromatography (fraction 8 with high molecular mass aggregates and fraction 14 with dimeric TACI-Fc). Cells were also treated with Atacicept (before size fractionation), a form of TACI-Fc unable to bind to Fc receptors. Cell activation was monitored by western blotting with an anti-phospho ERK1/2 antibody. Panel C. BAFF-sensitive BAFFR:Fas expressing cells were stimulated with the indicated concentration of BAFF 60-mer, in the presence or absence of Atacicept at a fixed concentration of 300 ng/ml. Cell viability was monitored with a colorimetric assay.
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Impaired TACI-Fc signalling in FcRγ−/− BMDMs.
2013Co-Authors: Josquin Nys, Cristian R. Smulski, Aubry Tardivel, Laure Willen, Christine Kowalczyk, Olivier Donzé, Bertrand Huard, Henry Hess, Pascal SchneiderAbstract:Bone marrow-derived macrophages from WT and FcRγ−/− C57BL/6 mice were stimulated for the indicated times with TACI-Fc at 10 µg/ml, Atacicept at 10 µg/ml, or with LPS at 50 ng/ml. Cell extracts were analyzed by western blotting with the indicated antibodies.
Nataliya Yeremenko - One of the best experts on this subject based on the ideXlab platform.
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A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells
Journal of Autoimmunity, 2016Co-Authors: Charlotte Hua, Michael Hahne, Rachel Audo, Nataliya Yeremenko, Dominique Baeten, Bernard Combe, Jacques Morel, Claire DaienAbstract:B cells may have a negative regulatory role, mainly mediated by interleukin 10 (IL-10). We recently showed that regulatory B-cell functions are impaired in patients with rheumatoid arthritis (RA) and that mice transgenic for a proliferation-inducing ligand (APRIL) are protected against collagen-induced arthritis. We aimed to explore the effect of APRIL on human B-cell IL-10 production, in healthy subjects and in patients with RA. The IL-10 production of B-cell was greater with APRIL than with BLyS or control medium, in a dose dependent manner. TACI expression was greater in IL-10 producing B cells (B10) than non-IL-10-producing B cells whereas BAFF-R expression was lower. TNF-α and IFN-γ secretion of T-cells were decreased by APRIL-stimulated B cells. APRIL stimulated STAT3 and STAT3 inhibition decreased B10 cells. APRIL also promoted B10 cells in RA patients. In conclusion, APRIL but not BLyS promotes IL-10 production by CpG-activated B cells and enhances the regulatory role of B cells on T cells. B10 cells in RA patients are responsive to APRIL, which suggests a possible therapeutic application of APRIL to expand B10 cells. This could also explain the difference of clinical efficacy observed between belimumab and Atacicept in RA.
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The TNF family member APRIL dampens collagen-induced arthritis
Annals of the Rheumatic Diseases, 2013Co-Authors: Leticia Fernandez, Nataliya Yeremenko, Bernard Combe, Jacques Morel, Gabriela Franco Salinas, Cecilia Rocha, Carla Carvalho-pinto, Laura Papon, Jan Paul Medema, Dominique BaetenAbstract:BACKGROUND: The tumour necrosis factor (TNF)-family members B cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) play important roles in B cell biology, and share binding to B cell maturation antigen and transmembrane activator and cyclophilin ligand interactor, both receptors of the TNF-family. However, while it is reported that BAFF can break B cell tolerance, the role of APRIL in autoimmunity remains elusive. OBJECTIVE: To evaluate the role of APRIL on collagen-induced arthritis (CIA). METHODS: CIA was induced in APRIL-transgenic (Tg) DBA/1 mice and littermates. Disease progression was evaluated by clinical and histological signs of arthritis. In another experimental setting mice were exposed to the collagen antibody-induced arthritis. In addition, we tested T cell dependent humoral responses in APRIL-Tg mice. RESULTS: We found that APRIL-Tg displayed a strongly reduced incidence and severity of CIA compared with littermates, with decreases in collagen-specific autoantibody titres, immune complex deposition and downstream mast cell activation in joints. Notably, ectopic APRIL-expression was also found to negatively regulate T cell dependent humoral responses. The lower autoantibody production in APRIL-Tg mice during CIA appears to be crucial, as arthritis induced by administration of anti-collagen antibodies developed similar in APRIL-Tg and control mice, thus demonstrating that the downstream effector pathways induced by anti-collagen antibodies remain intact in APRIL-Tg mice. This protective effect was specifically mediated by APRIL, as adenoviral delivery of APRIL decreased CIA in a therapeutic setting. CONCLUSIONS: Collectively, our data identify APRIL as a negative regulator of CIA by regulating autoantibody production. These findings are of important clinical relevance, as the therapeutic potential of transmembrane activator and cyclophilin ligand interactor-Fc (Atacicept) is presently evaluated in clinical trials.