Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients

Rice, Lisa; Padilla, Cristina; McLaughlin, Sarah; Mathes, Allison; Ziemek, Jessica; Goummih, Salma; Nakerakanti, Sashidhar; York, Michael; Farina, Giuseppina; Whitfield, Michael L.; Spiera, Robert; Christmann, Romy B.; Gordon, Jessica; Weinberg, Janice; Simms, Robert W.; Lafyatis, Robert

doi:10.1172/jci77958

Cited by 292 publications

(227 citation statements)

References 51 publications

(50 reference statements)

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“…Our results show that pericytes of patients with SSc express the activated form of ADAM12 molecule, and that TGF-β, the main profibrotic cytokine in SSc 26,35,36,37,38 , modulates ADAM12 expression on these cells. These data suggest that, as observed in other experimental models of fibrosis, perivascular cells may be committed to transdifferentiate toward activated myofibroblasts and are involved in the fibrotic lesions of SSc.…”

Section: Discussionmentioning

confidence: 67%

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Cipriani

Benedetto²,

Ruscitti³

et al. 2016

J Rheumatol

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Objective.Microvascular damage is pivotal in the pathogenesis of systemic sclerosis (SSc), preceding fibrosis, and whose trigger is not still fully understood. Perivascular progenitor cells, with profibrotic activity and function, are identified by the expression of the isoform 12 of ADAM (ADAM12) and this molecule may be upregulated by transforming growth factor-β (TGF-β). The goal of this work was to evaluate whether pericytes in the skin of patients with diffuse cutaneous SSc (dcSSc) expressed ADAM12, suggesting their potential contribution to the fibrotic process, and whether TGF-β might modulate this molecule.Methods.After ethical approval, mesenchymal stem cells (MSC) and fibroblasts (FB) were isolated from bone marrow and skin samples collected from 20 patients with dcSSc. ADAM12 expression was investigated in the skin and in isolated MSC and FB treated with TGF-β by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-β modulation.Results.Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-β in vitro treatment induced a significant increase of ADAM12 in both SSc-MSC and -FB, with the higher levels observed in dcSSc cells. After ADAM12 silencing, the TGF-β ability to upregulate α-smooth muscle actin in both SSc-MSC and SSc-FB was inhibited.Conclusion.Our results suggest that in SSc, pericytes that transdifferentiate toward activated FB are present in the vascular tree, and TGF-β, while increasing ADAM12 expression, may modulate this transdifferentiation.

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Section: Discussionmentioning

confidence: 67%

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Cipriani

Benedetto²,

Ruscitti³

et al. 2016

J Rheumatol

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“…33 Two separate data sets were obtained using the same U133A 2.0 chip (Affymetrix, Santa Clara, CA). 33,34 These data were normalized for batch differences using the ComBat algorithm (SVA 3.18 package; Bioconductor http://www.bioconductor.org/packages/release/BiocViews. html#_Software).…”

Section: Patient Specimensmentioning

confidence: 99%

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

Nazari

Rice

Stifano

et al. 2016

The American Journal of Pathology

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Tissue injury triggers the activation and differentiation of multiple cell types to minimize damage and initiate repair processes. In systemic sclerosis, these repair processes appear to run unchecked, leading to aberrant remodeling and fibrosis of the skin and multiple internal organs, yet the fundamental pathological defect remains unknown. We describe herein a transition wherein the abundant CD34 þ dermal fibroblasts present in healthy human skin disappear in the skin of systemic sclerosis patients, and CD34 À , podoplanin þ , and CD90 þ fibroblasts appear. This transition is limited to the upper dermis in several inflammatory skin diseases, yet in systemic sclerosis, it can occur in all regions of the dermis. In vitro, primary dermal fibroblasts readily express podoplanin in response to the inflammatory stimuli tumor necrosis factor and IL-1b. Furthermore, we show that on acute skin injury in both human and murine settings, this transition occurs quickly, consistent with a response to inflammatory signaling. Transitioned fibroblasts partially resemble the cells that form the reticular networks in organized lymphoid tissues, potentially linking two areas of fibroblast research. These results allow for the visualization and quantification of a basic stage of fibroblast differentiation in inflammatory and fibrotic diseases in the skin. (Am J Pathol 2016, 186: 2650e2664; http://dx

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“…In recent years, experimental models focusing on the fibrotic remodeling component of SSc have highlighted a role for the TGF-b pathway (5)(6)(7)(8). Direct targeting of this critical pathway has proved a complex undertaking due to anti-inflammatory and wound healing activities of TGF-b (9), but recent demonstration of clinical improvement in SSc patients treated with fresolimumab supports a fibrogenic role for TGF-b in human disease (10).…”

mentioning

confidence: 99%

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Delaney¹,

Morehouse²,

Brohawn³

et al. 2016

The Journal of Immunology

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Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-α levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma.

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Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients

Cited by 292 publications

References 51 publications

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

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