Cellular Therapies in Systemic Sclerosis: Recent Progress

Rhijn-Brouwer, Femke C C van; Gremmels, Hendrik; Fledderus, Joost O.; Radstake, Timothy R. D. J.; Verhaar, Marianne C.; Laar, Jacob M van

doi:10.1007/s11926-015-0555-7

Cited by 21 publications

(16 citation statements)

References 91 publications

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“…In the present study, we found that Sema4A induced the expression of ECM components and α‐SMA by healthy control and SSc patient dermal fibroblasts, effects mediated by the receptors plexin D1 and plexin B2. In conclusion, in this study we have identified Sema4A as a key mediator of Th17 production and fibrosis, and blocking Sema4A signaling might suppress both pathologic processes in SSc, a complex and heterogeneous disease for which currently available therapies can only treat organ manifestations and no antifibrotic drugs have yet to be approved .…”

Section: Discussionmentioning

confidence: 71%

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

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Objective To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc). Methods Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme‐linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6–7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5–7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay. Results Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up‐regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. Conclusion Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.

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Section: Discussionmentioning

confidence: 71%

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

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“…In conclusion, targeting IL-17 signaling might be a potential option in the treatment of systemic rheumatic diseases, which is highly important due to the need for new therapeutic options for these diseases, as an effective therapy is lacking for SLE, SSc and SS patients. The most common therapies are broad-spectrum immunosuppressive drugs, which have moderate to severe side effects and therapies that only treat organ manifestations or simply relieve the clinical symptoms [ 49 , 130 , 131 , 132 , 133 ]. However, the ongoing clinical trials with different IL-17 inhibitors need to be finished before concluding whether IL-17 blocking is an effective therapeutic strategy for these diseases.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Blocking IL-17: A Promising Strategy in the Treatment of Systemic Rheumatic Diseases

Rafael-Vidal

Pérez

Altabás

et al. 2020

IJMS

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Systemic rheumatic diseases are a heterogeneous group of autoimmune disorders that affect the connective tissue, characterized by the involvement of multiple organs, leading to disability, organ failure and premature mortality. Despite the advances in recent years, the therapeutic options for these diseases are still limited and some patients do not respond to the current treatments. Interleukin-17 (IL-17) is a cytokine essential in the defense against extracellular bacteria and fungi. Disruption of IL-17 homeostasis has been associated with the development and progression of rheumatic diseases, and the approval of different biological therapies targeting IL-17 for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) has highlighted the key role of this cytokine. IL-17 has been also implicated in the pathogenesis of systemic rheumatic diseases, including systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS) and systemic sclerosis (SSc). The aim of this review is to summarize and discuss the most recent findings about the pathogenic role of IL-17 in systemic rheumatic and its potential use as a therapeutic option.

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“…In the last decade, cellular therapy such as multipotential stromal cells (MSCs) has been used extensively for immunomodulation in the variety of clinical settings including graft-versus-host disease (GVHD), Crohn’s disease, rheumatoid arthritis, kidney transplantation, type II diabetes and multiple sclerosis with promising outcomes 1 – 3 . MSCs are imbued with remarkable in vitro and in vivo immunomodulatory properties although initially defined based on their clonogenicity, high proliferative capacity and potential for trilineage differentiation to the bone, cartilage and fat lineages 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

T cell immunomodulation by clinically used allogeneic human cancellous bone fragments: a potential novel immunotherapy tool

El-Sherbiny

El-Jawhari

Moseley

et al. 2018

Sci Rep

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Multipotential stromal cells (MSCs) demonstrate strong immunomodulation capabilities following culture expansion. We have previously demonstrated that human cancellous bone fragments (CBFs) clinically used as viable allografts for spinal fusion have resident MSCs that exhibit T cell immunomodulation after monolayer expansion. This study investigated the immunomodulatory ability of these CBFs without MSC culture-expansion. CD4 positive T cells were induced to proliferate using CD3/CD28 stimulation and added to CBFs at different ratios of T cells per gram of CBF. A dose-dependent suppressive effect on T cell proliferation was evident and correlated with increased culture supernatant levels of TGF-ß1, but not PGE2. CBF-driven immunosuppression was reduced in co-cultures with TGF-ß neutralising antibodies and was higher in cell contact compared to non-contact cultures. CBF gene expression profile identified vascular cell adhesion molecule-1, bone marrow stromal antigen 2/CD317 and other interferon signalling pathway members as potential immunomodulatory mediators. The CD317 molecule was detected on the surface of CBF-resident cells confirming the gene expression data. Taken together, these data demonstrate that human clinically used CBFs are inherently immunomodulatory and suggest that these viable allografts may be used to deliver therapeutic immunomodulation for immune-related diseases.

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Cellular Therapies in Systemic Sclerosis: Recent Progress

Cited by 21 publications

References 91 publications

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Blocking IL-17: A Promising Strategy in the Treatment of Systemic Rheumatic Diseases

T cell immunomodulation by clinically used allogeneic human cancellous bone fragments: a potential novel immunotherapy tool

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