scholarly journals B lymphocyte stimulator modulates number and function of endothelial progenitor cells in systemic lupus erythematosus

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Francesca Romana Spinelli ◽  
Cristiana Barbati ◽  
Fulvia Cecarelli ◽  
Francesca Morello ◽  
Tania Colasanti ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Endothelial Cells ◽  
B Cell ◽  
Progenitor Cells ◽  
Lupus Erythematosus ◽  
B Lymphocyte ◽  
Ex Vivo ◽  
Systemic Lupus ◽  
B Lymphocyte Stimulator

Abstract Background Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial function. In patients with systemic lupus erythematosus (SLE), the numerical reduction and functional impairment of EPCs contribute to the endothelial dysfunction. Through ex vivo and in vitro studies, we aimed at evaluating the effects of B lymphocyte stimulator (BLyS) on EPC colonies and endothelial cells and also investigating BLyS receptor expression on these cells. Methods EPCs were isolated from peripheral blood mononuclear cells (PBMC). In order to evaluate their ability to form colonies, EPCs were cultured on fibronectin-coated dishes and incubated with BlyS alone or BlyS and belimumab. Apoptosis of EPCs and endothelial cell line EA.hy926 was evaluated after 6, 12, and 24 h of incubation with BLyS and after 6 h with BLyS and belimumab. The expression of B cell activating factor-receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) on EPCs and EA.hy926 was analyzed by cytofluorimetry. Results The number of EPC colonies was lower in patients than in controls. Moreover, the colonies from SLE patients were poorly organized compared to controls; the addition of belimumab restored the colony structure. Incubation with BLyS induced apoptosis of EPCs and EA.hy926 that was inhibited by the co-incubation with belimumab. BAFF-R and BCMA were expressed on both EPCs and EA.hy926, while TACI was expressed only on EPCs. Conclusions EPCs and endothelial cells preferentially express BAFF-R which could be involved in the pro-apoptotic effect of BlyS. Belimumab administration seems to restore the quantitative and qualitative changes of EPC colonies both ex vivo and in vitro.

scholarly journals OP0039 ALPN-303, AN ENHANCED, POTENT DUAL BAFF/APRIL ANTAGONIST ENGINEERED BY DIRECTED EVOLUTION FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER B CELL-RELATED AUTOIMMUNE DISEASES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 21.2-21
Author(s):  
S. R. Dillon ◽  
L. S. Evans ◽  
K. E. Lewis ◽  
J. Yang ◽  
M. W. Rixon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
B Cell ◽  
Directed Evolution ◽  
Human Lymphocyte ◽  
Lupus Erythematosus ◽  
Plasma Cells ◽  
Systemic Lupus ◽  
Cynomolgus Monkeys

Background:BAFF and APRIL are TNF superfamily members that form homo- and heteromultimers that bind TACI and BCMA on B cells; BAFF also binds BAFF-R. BAFF and APRIL support B cell development, differentiation, and survival, particularly for plasmablasts and plasma cells, and play critical roles in the pathogenesis of B cell-related autoimmune diseases. In nonclinical models, inhibition of either BAFF or APRIL alone mediates relatively modest effects, whereas their co-neutralization dramatically reduces B cell function, including antibody production. Fc fusions of wild-type (WT) TACI (e.g. atacicept and telitacicept) target both BAFF and APRIL and have demonstrated promising clinical potential in e.g. systemic lupus erythematosus (SLE) and IgA nephropathy but have not yet clearly exhibited long-term and/or complete disease remissions.Objectives:To generate a dual BAFF/APRIL antagonist with inhibitory activity superior to WT TACI and BCMA and with the potential to improve clinical outcomes in B cell-mediated diseases.Methods:Our directed evolution platform was used to identify a potent variant TNFR domain (vTD) of TACI that exhibits significantly enhanced affinity for BAFF and APRIL as compared to WT TACI; this TACI vTD domain was fused to a human IgG Fc to generate the therapeutic candidate ALPN-303. ALPN-303 was evaluated for functional activity in: 1) human lymphocyte assays, 2) the NOD.Aec1Aec2 spontaneous model of Sjogren’s syndrome (SjS), 3) the bm12-induced mouse model of lupus, 4) the (NZB/NZW)F1 spontaneous model of lupus, and 5) preclinical rodent and cynomolgus monkey pharmacokinetic/pharmacodynamic studies.Results:ALPN-303 inhibited BAFF- and APRIL-mediated signaling in vitro in human lymphocyte assays, with significantly lower IC50 values than WT TACI-Fc and belimumab comparators. In all mouse models evaluated, administration of ALPN-303 rapidly and significantly reduced key lymphocyte subsets including plasma cells, germinal center B cells, and follicular T helper cells. ALPN-303 significantly reduced autoantibodies and sialadenitis in the spontaneous SjS model, inhibited glomerular IgG deposition in the bm12-induced model of lupus, and potently suppressed anti-dsDNA autoAbs, blood urea nitrogen levels, proteinuria, sialadenitis, kidney lesions, and renal immune complex deposition in the NZB/W lupus model. As compared to WT TACI-Fc, ALPN-303 exhibited higher serum exposure and significantly and persistently decreased titers of serum IgM, IgG, and IgA antibodies in mice and cynomolgus monkeys (Figure 1).Figure 1.ALPN-303 induces more potent suppression, as compared to WT TACI-Fc, of serum immunoglobulins following a single 9 mg/kg IV infusion (on Day 0; arrows) in female cynomolgus monkeys.Conclusion:ALPN-303 is a potent BAFF/APRIL antagonist derived from our directed evolution platform that consistently demonstrates encouraging immunomodulatory activity and efficacy in vitro and in vivo, superior in preclinical studies to anti-BAFF antibody and WT TACI-Fc. This novel Fc fusion molecule demonstrates favorable preliminary developability characteristics, including higher serum exposures and more potent immunosuppressive activities, which may enable lower clinical doses and/or longer dosing intervals than WT TACI-Fc therapeutics. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell-related diseases such as SLE, SjS, and other connective tissue diseases. Preclinical development is underway to enable the initiation of clinical trials later this year.Disclosure of Interests:Stacey R. Dillon Shareholder of: Alpine Immune Sciences, Bristol Myers Squibb, Employee of: Alpine Immune Sciences, Bristol Myers Squibb, Lawrence S. Evans Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Katherine E. Lewis Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jing Yang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Mark W. Rixon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Joe Kuijper Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Dan Demonte Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Janhavi Bhandari Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Steve Levin Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Kayla Kleist Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Sherri Mudri Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Susan Bort Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Daniel Ardourel Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Michelle A. Seaberg Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Rachel Wang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Chelsea Gudgeon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Russell Sanderson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Martin F. Wolfson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jan Hillson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Stanford L. Peng Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences

scholarly journals B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients

2009 ◽  
Vol 60 (11) ◽  
pp. 3400-3409 ◽  
Author(s):  
Sandy D. Hong ◽  
Andreas Reiff ◽  
Hai-Tao Yang ◽  
Thi-Sau Migone ◽  
Christopher D. Ward ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Juvenile Idiopathic Arthritis ◽  
Lupus Erythematosus ◽  
B Lymphocyte ◽  
Systemic Lupus ◽  
Pediatric Systemic Lupus Erythematosus ◽  
B Lymphocyte Stimulator

Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus

2015 ◽  
Vol 75 (4) ◽  
pp. 739-747 ◽  
Author(s):  
Sarah A Jones ◽  
Andrew E J Toh ◽  
Dragana Odobasic ◽  
Marie-Anne Virginie Oudin ◽  
Qiang Cheng ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Leucine Zipper ◽  
Germinal Centre ◽  
Cell Phenotype ◽  
Systemic Lupus ◽  
Human B Cells

ObjectivesSystemic lupus erythematosus (SLE) is a serious multisystem autoimmune disease, mediated by disrupted B cell quiescence and typically treated with glucocorticoids. We studied whether B cells in SLE are regulated by the glucocorticoid-induced leucine zipper (GILZ) protein, an endogenous mediator of anti-inflammatory effects of glucocorticoids.MethodsWe conducted a study of GILZ expression in blood mononuclear cells of patients with SLE, performed in vitro analyses of GILZ function in mouse and human B cells, assessed the contributions of GILZ to autoimmunity in mice, and used the nitrophenol coupled to keyhole limpet haemocyanin model of immunisation in mice.ResultsReduced B cell GILZ was observed in patients with SLE and lupus-prone mice, and impaired induction of GILZ in patients with SLE receiving glucocorticoids was associated with increased disease activity. GILZ was downregulated in naïve B cells upon stimulation in vitro and in germinal centre B cells, which contained less enrichment of H3K4me3 at the GILZ promoter compared with naïve and memory B cells. Mice lacking GILZ spontaneously developed lupus-like autoimmunity, and GILZ deficiency resulted in excessive B cell responses to T-dependent stimulation. Accordingly, loss of GILZ in naïve B cells allowed upregulation of multiple genes that promote the germinal centre B cell phenotype, including lupus susceptibility genes and genes involved in cell survival and proliferation. Finally, treatment of human B cells with a cell-permeable GILZ fusion protein potently suppressed their responsiveness to T-dependent stimuli.ConclusionsOur findings demonstrated that GILZ is a non-redundant regulator of B cell activity, with important potential clinical implications in SLE.

Belimumab restores Treg/Th17 balance in patients with refractory systemic lupus erythematosus

Lupus ◽  
2018 ◽  
Vol 27 (12) ◽  
pp. 1926-1935 ◽  
Author(s):  
M Prete ◽  
P Leone ◽  
M A Frassanito ◽  
V Desantis ◽  
C Marasco ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Standard Therapy ◽  
B Lymphocyte ◽  
Specific Inhibitor ◽  
The United States ◽  
Systemic Lupus ◽  
The Mean

Belimumab, a specific inhibitor of the soluble B lymphocyte stimulator (BlyS), is the first biological drug approved by the United States Food and Drug Administration for the treatment of patients with active systemic lupus erythematosus (SLE) refractory to standard therapy. Given that an imbalance between regulatory T cells (Treg) and interleukin (IL)-17A-secreting T cells (Th17) has been reported in various autoimmune disorders, we assessed the frequency of both Treg and Th17 peripheral blood populations before and after belimumab administration in 20 patients with active SLE refractory to standard therapy. After six months of treatment, the mean SELENA-SLEDAI score as well as the mean anti-double-stranded DNA antibody titers were significantly decreased. In addition, we observed a significant increase in Treg percentages and a parallel, significant decrease in Th17 percentages, accompanied by significantly reduced serum levels of IL-21. In vitro studies showed that Treg purified from belimumab-treated patients were fully functional and displayed a suppressor function similar to that of Treg purified from healthy donors. Belimumab can restore Treg/Th17 balance in SLE patients with uncontrolled disease activity, and this results in decreased flare rate and reduced glucocorticoid dosage.

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