scholarly journals B-Cell Depletion Therapy in Systemic Sclerosis: Experimental Rationale and Update on Clinical Evidence

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Dimitrios Daoussis ◽  
Stamatis-Nick C. Liossis ◽  
Georgios Yiannopoulos ◽  
Andrew P. Andonopoulos
Keyword(s):  
Animal Model ◽  
Systemic Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Clinical Efficacy ◽  
Randomized Study ◽  
Skin Fibrosis ◽  
Open Label ◽  
Fibrotic Process ◽  
Lung Biopsies

Systemic sclerosis (SSc) is a systemic rheumatic disease with poor prognosis since therapeutic options are limited. Recent evidence from animal models suggests that B-cells may be actively involved in the fibrotic process. B-cells from tight skin mice, an animal model of scleroderma, display a “hyperresponsive” phenotype; treatment with rituximab (RTX) significantly attenuates skin fibrosis in this animal model. In humans, B-cell infiltration is a prominent finding in most lung biopsies obtained from patients with SSc-associated interstitial lung disease. Several open label studies have assessed the clinical efficacy of RTX in SSc. In most patients skin fibrosis improved; lung function either improved or remained stable. Definite conclusions regarding the clinical efficacy of RTX in SSc cannot be drawn but further exploration with a multicenter, randomized study is warranted.

scholarly journals Clinical Efficacy and Safety of Injection of Stromal Vascular Fraction Derived from Autologous Adipose Tissues in Systemic Sclerosis Patients with Hand Disability: A Proof-Of-Concept Trial

2020 ◽  
Vol 9 (9) ◽  
pp. 3023
Author(s):  
Youngjae Park ◽  
Yoon Jae Lee ◽  
Jung Hee Koh ◽  
Jennifer Lee ◽  
Hong-Ki Min ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Clinical Efficacy ◽  
Stromal Vascular Fraction ◽  
Skin Fibrosis ◽  
Therapeutic Modality ◽  
Efficacy And Safety ◽  
Open Label ◽  
Adipose Tissues ◽  
Hand Disability

Background: Stromal vascular fraction (SVF) has recently emerged as a potential therapeutic modality, due to its multipotent cellular components in tissue regeneration. Systemic sclerosis (SSc) is a progressive autoimmune disease that results in hand disability by skin fibrosis and microangiopathies. We performed an open-label study to investigate the efficacy and safety of SVF injection in SSc patients (Clinical Trial number: NCT03060551). Methods: We gathered 20 SSc patients with hand disability, planning for a 24-week follow-up period. SVF was extracted from autologous adipose tissues, processed by the closed system kit, and injected into each finger of SSc patients. We observed various efficacy and safety profiles at each follow-up visit. Results: Among the 20 initially enrolled patients, eighteen received SVF injection, and were completely followed-up for the whole study period. Patients received 3.61 × 106 mesenchymal stem cells into each finger on average. Skin fibrosis, hand edema, and quality of life were significantly improved, and 31.6% of active ulcers were healed at 24 weeks after injections. Semiquantitative results of nailfold capillary microscopy were ameliorated. There was no single serious adverse event related to the procedure. Conclusions: Injection of SVF derived from autologous adipose tissues is tolerable, and shows clinical efficacy in SSc patients.

scholarly journals Effect of bosentan on skin fibrosis in patients with systemic sclerosis: a prospective, open-label, non-comparative trial

Rheumatology ◽  
2010 ◽  
Vol 49 (7) ◽  
pp. 1336-1345 ◽  
Author(s):  
A. Kuhn ◽  
M. Haust ◽  
V. Ruland ◽  
R. Weber ◽  
P. Verde ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Comparative Trial ◽  
Skin Fibrosis ◽  
Open Label

scholarly journals Generation of Monoclonal Antibodies against Immunoglobulin Proteins of the Domestic Ferret (Mustela putorius furo)

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Greg A. Kirchenbaum ◽  
Ted M. Ross
Keyword(s):  
Animal Model ◽  
Monoclonal Antibodies ◽  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Unmet Need ◽  
Mustela Putorius ◽  
Peripheral Blood Mononuclear ◽  
Antibody Secreting Cells ◽  
Mustela Putorius Furo

The domestic ferret (Mustela putorius furo) serves as an animal model for the study of several viruses that cause human disease, most notably influenza. Despite the importance of this animal model, characterization of the immune response by flow cytometry (FCM) is severely hampered due to the limited number of commercially available reagents. To begin to address this unmet need and to facilitate more in-depth study of ferret B cells including the identification of antibody-secreting cells, eight unique murine monoclonal antibodies (mAb) with specificity for ferret immunoglobulin (Ig) were generated using conventional B cell hybridoma technology. These mAb were screened for reactivity against ferret peripheral blood mononuclear cells by FCM and demonstrate specificity for CD79β+B cells. Several of these mAb are specific for the light chain of surface B cell receptor (BCR) and enable segregation of kappa and lambda B cells. Additionally, a mAb that yielded surface staining of nearly all surface BCR positive cells (i.e., pan ferret Ig) was generated. Collectively, these MαF-Ig mAb offer advancement compared to the existing portfolio of polyclonal anti-ferret Ig detection reagents and should be applicable to a wide array of immunologic assays including the identification of antibody-secreting cells by FCM.

scholarly journals Increased Frequency of Activated Switched Memory B Cells and Its Association With the Presence of Pulmonary Fibrosis in Diffuse Cutaneous Systemic Sclerosis Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Diána Simon ◽  
Péter Balogh ◽  
Szabina Erdő-Bonyár ◽  
Katalin Böröcz ◽  
Tünde Minier ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
B Cells ◽  
Pulmonary Fibrosis ◽  
B Cell ◽  
Topoisomerase I ◽  
Citrate Synthase ◽  
Severe Form ◽  
Memory B Cells ◽  
Autoantibody Production ◽  
B Cell Subsets

Disease-associated, high-affinity pathological autoantibody production is a well-described consequence of immune dysregulation affecting B cells in systemic sclerosis (SSc), including the distribution of B-cell subsets. We have previously shown that the increased relative frequency of CD19+CD27+IgD− switched memory B cells is associated with the severe form of SSc. This study sought to analyze memory B cell subsets using an extended range of markers for further subdivision based on CD19, IgD, CD27, CD38 and CD95 phenotype, to define relationship between the alterations of memory B cell subsets and the clinical features of SSc. Peripheral blood samples were obtained from 21 SSc patients, including 14 diffuse (dcSSc) and 7 limited (lcSSc) cutaneous SSc patients, with disease duration of 2.7 ( ± 1.6) years. After purification of CD19+ B cells, multiparametric flow cytometry was performed and the frequencies of CD19+IgD−CD27−CD38+ double negative (DN) 1, CD19+IgDloCD27+CD38+ unswitched, CD19+IgD−CD27+CD38+CD95− resting switched and CD19+IgD−CD27+CD38−CD95+ activated switched memory (ASM) B cells were determined, and correlated with clinical features of SSc. The dcSSc patients had a higher frequency of ASM B cells (p = 0.028) compared to lcSSc patients. The percentage of ASM B cells was elevated in anti-Scl-70 (anti-topoisomerase I) antibody positive patients compared to negative patients (p = 0.016). Additionally, the frequency of ASM B cells was also increased in patients with pulmonary fibrosis (p = 0.003) suggesting that patients with severe form of SSc have higher ASM B cell ratios. Furthermore, the ratio of DN1 B cells was decreased (p = 0.029), while the level of anti-citrate synthase IgG natural autoantibody was elevated (p = 0.028) in patients with active disease. Our observations on the increase of ASM B cells in dcSSc and in patients with pulmonary fibrosis may point to the association of this alteration with the severe form of the disease. Functionally the correlation of ASM B cells as effector memory-plasma cell precursors with anti-topoisomerase I antibody positivity could reflect their contribution to pathological autoantibody production, whereas the decrease of memory precursor DN B cells and the increase of anti-citrate synthase IgG autoantibody may have potential significance in the assessment of disease activity.

scholarly journals AB0029 INHIBITION OF EFFECTOR B CELLS BY IBRUTINIB IN SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1317.1-1318
Author(s):  
J. Einhaus ◽  
A. C. Pecher ◽  
E. Asteriti ◽  
H. Schmid ◽  
K. A. Secker ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Transcription Factor ◽  
Systemic Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Therapeutic Potential ◽  
Controlled Trial ◽  
Intracellular Cytokine Staining ◽  
Disease Onset ◽  
Innate Immune

Background:Systemic sclerosis (SSc) is a connective tissue disease with significant morbidity and mortality. Effective treatment is still missing, and clinical control of the disease remains challenging. In particular, the development of pulmonary and cardiac fibrosis and pulmonary hypertension are severe complications responsible for excessive mortality. Currently available treatment strategies – besides aggressive autologous stem cell transplantation which is an option only for selected patients – only alleviate symptoms and slow disease progression. Previous attempts of immunomodulating therapies addressing B cell pathology like rituximab and tocilizumab in SSc showed mixed efficacy1,2Objectives:Here, we investigated the therapeutic potential of ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor used in B cell malignancies, to alter B cell pathology in SSc in anin vitromodel of autoimmunity.Methods:PBMCs and sorted B cells of 24 patients with SSc were used for functional testing after stimulation with hypomethylated DNA fragments (CpG) to induce an innate immune response. The effects of ibrutinib on cytokine production, autoantibody release and activation of the transcription factor NFκB were evaluated via multiplex cytokine assay, ELISA and flow cytometry.Results:Ibrutinib was able to reduce the production of the profibrotic hallmark cytokines IL-6 and TNF-α, which are mainly released by the effector B cell population, in response to TLR9-stimulation. Importantly, small doses of ibrutinib (0.1 µM) preserved the production of immunoregulatory IL-10 and IFN-γ while effectively inhibiting the cardinal cytokines of hyperactivated profibrotic effector B cells in SSc. Intracellular cytokine staining of IL-6 in B cell subsets further endorsed the potential of ibrutinib to inhibit B cells in a subset-specific manner, reducing IL-6+naïve B cells significantly but not IL-6+memory B cells. The subset specificity was abolished when high doses of ibrutinib (10 µM) were applied. In a flow cytometry analysis of phosphorylated NFκB, an important transcription factor in the induction of innate immune responses in B cells, significantly less activation was observed with ibrutinib treatment (0.1 µM). Higher doses of ibrutinib were unable to further reduce the abundance of pNFκB.Conclusion:Our data could pave the avenue for a clinical application of ibrutinib for patients with SSc as a novel treatment option for the underlying pathogenetic immune imbalance contributing to disease onset and progression.References:[1]Khanna, D.et al.Efficacy and Safety of Tocilizumab for the Treatment of Systemic Sclerosis: Results from a Phase 3 Randomized Controlled Trial [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10).[2]Jordan, S.et al.Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group.Ann. Rheum. Dis.74, 1188–1194 (2015).Disclosure of Interests:Jakob Einhaus: None declared, Ann-Christin Pecher: None declared, Elisa Asteriti: None declared, Hannes Schmid: None declared, Kathy-Ann Secker: None declared, Silke Duerr-Stoerzer: None declared, Hildegard Keppeler: None declared, Reinhild Klein: None declared, Corina Schneidawind: None declared, Jörg Henes Grant/research support from: Novartis, Roche-Chugai, Consultant of: Novartis, Roche, Celgene, Pfizer, Abbvie, Sanofi, Boehringer-Ingelheim,, Dominik Schneidawind: None declared

scholarly journals Rituximab in systemic sclerosis

2021 ◽  
Vol 30 (2) ◽  
pp. 31-35
Author(s):  
T. Shevtsova ◽  
V. Nadtocheeva ◽  
S. Nimiritskaya ◽  
L. Akulkina ◽  
N. Bulanov ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Systemic Sclerosis ◽  
B Cells ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Skin Fibrosis

To evaluate the effect of intravenous rituximab, a monoclonal antibody to B-cells, on interstitial lung disease, skin fibrosis and arthritis in patients with systemic sclerosis (SSc).

scholarly journals CpG-activated Regulatory B-cell Progenitors Alleviate Murine Sclerodermatous Chronic GVHD

2021 ◽  
Author(s):  
Viviane A Agbogan ◽  
Pauline Gastineau ◽  
Emmanuel Tejerina ◽  
Saoussen Karray ◽  
Flora Zavala
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Bone Marrow Cells ◽  
Cytokine Expression ◽  
Skin Fibrosis ◽  
Disease Symptoms ◽  
Regulatory B Cell

Abstract BackgroundDevelopment of chronic Graft Versus Host Disease (cGVHD) represents a major impediment in allogeneic hematopoietic stem cell transplantation (HSCT). This disorder is associated with severe impairment of B-cell homeostasis, regulatory B-cell function and distribution. Conversely, the presence of bone marrow and circulating hematogones is associated with reduced GVHD risks. These findings raised the question whether B-cell progenitors, which provide protection in various autoimmune disease models following activation with the TLR-9 agonist CpG (CpG-proBs), could likewise reduce disease symptoms in a sclerodermatous model of cGVHD. MethodsChronic sclerodermatous GVHD was induced in irradiated Balb/c recipients reconstituted with T- and B-cell-depleted bone marrow cells and splenocytes from C57BL/6J donors. CpG-proB-cell progenitors sorted from in vitro CpG-activated bone marrow cells were then adoptively transferred into GVHD recipients. Their effect on disease symptoms, such as diarrhea, skin fibrosis and survival was evaluated in the therapeutic window defined beforehand. Transferred progenitors were analyzed for migration, differentiation and cytokine expression using flow cytofluorimetric methods, which were also used to establish their impact on T-cell cytokine expression and follicular helper/regulatory T-cell ratios (Tfh/Tfr) in peripheral and mesenteric lymph nodes. Skin fibrosis was assessed by histology, identification of infiltrating cells and gene expression profiles of cytokines and molecules involved in the fibrotic process, using qRT-PCR microarrays in all tissue samples.ResultsWe found that CpG-proBs, adoptively transferred during the initial phase of disease, reduced the diarrhea score and mostly prevented cutaneous fibrosis. Progenitors migrated to the draining lymph nodes and to the skin where they mainly differentiated into follicular B cells. CpG activation and IFN-γ expression were required for the protective effect, which resulted in reduced CD4+ T-cell-derived production of cytokines critically involved in cGVHD, such as TGF-β, IL-13 and IL-21. Adoptive transfer increased the Tfr/Tfh ratio. Moreover, CpG-proBs privileged the accumulation of IL-10-positive CD8+ T cells, B cells and dendritic cells in the skin. ConclusionOur findings support the notion that adoptively transferred CpG-proBs provide an efficient strategy for alleviating sclerodermatous cGVHD either per se or as a beneficial adjunct to the HSC graft.

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