Sclerotic GvHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody
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ABSTRACT:
PROVIDER: PRJNA1310510 | ENA |
REPOSITORIES: ENA
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Project description:Immune driven fibrotic skin diseases including scleroderma/systemic sclerosis (SSc) and chronic graft-versus-host-disease (cGvHD) cause skin stiffening that has major impact on patient quality of life and associated patient mortality. Therapies to improve sclerotic skin resulting from these diseases are largely ineffective. We previously showed that EREG, a DC3 dendritic cell-derived EGFR ligand, is elevated in the skin and lung of patients with SSc and required for maintenance of skin fibrosis. Here, we developed a fully human anti-EREG neutralizing antibody that has both high affinity and specificity. We found this therapeutic antibody to be functional and safe in vivo using human EREG knock-in mice. To understand the antifibrotic mechanism of targeting EREG, we aligned skin single-cell transcriptomic profiles of SSc, morphea (localized scleroderma) and SclGvHD with disease biomarkers. EREG expression in the skin was elevated in all three fibrotic diseases and a driver of TNC production by myofibroblasts in all three fibrotic diseases. TNC is a pro-inflammatory extracellular glycoprotein that functions as an endogenous TLR4 ligand which induces expression of TLR4 target genes CCL2 and IL6. Examination of skin explants from patients with active SclGvHD treated with anti-EREG therapeutic antibody by spatial transcriptomics demonstrated upregulation of matrix degradation by increased MMP and decreased TIMP1 expression. Protein measurements showed reduced secretion of EREG targets TNC, CCL2, and TIMP1 in all patients, and type I collagen and FN1 in 3/4 patients. Thus, sclerotic skin treated with the anti-EREG therapeutic antibody reduced inflammatory and fibrosis biomarkers associated with EGFR and TLR4 signaling.
2025-08-29 | GSE306357 | GEO
Project description:RNA expression profiling was carried out for systemic sclerosis (scleroderma) on skin biopsies obtained from both diffuse scleroderma (dcSSc) and limited scleroderma (lcSSc) subjects patients and compared to normal subjects. The patient group comprised of 4 dcSSc and 2 lcSSc subjects, all of whom were Caucasian and belonged to the age range of 42-73 (Mean age = 61.6). Patient sample set consisted of 3 females and 3 males. Race matched female volunteers from the same geographical area were recruited as controls (n = 4) and belonged to the age range of 41-62 (Mean age = 52).
2015-03-25 | E-MEXP-1214 | biostudies-arrayexpress
Project description:Fibroblast were isolated from either back or forearm punch biopsies taken by Dr. Kari Connolly(UCSF) from either normal control patients, patients with a diagnosis of Systemic Sclerosis with Diffuse Scleroderma and patients with a diagnosis of morphea. Scleroderma fibroblast were grown to confluence, media was changed and the RNA prepared from the cells 48 hrs later (to avoid serum responsive genes). A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design
2005-12-21 | GSE3886 | GEO
Project description:Fibroblast were isolated from either back or forearm punch biopsies taken by Dr. Kari Connolly(UCSF) from either normal control patients, patients with a diagnosis of Systemic Sclerosis with Diffuse Scleroderma and patients with a diagnosis of morphea. Scleroderma fibroblast were grown to confluence, media was changed and the RNA prepared from the cells 48 hrs later (to avoid serum responsive genes). A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. User Defined
2005-12-20 | E-GEOD-3886 | biostudies-arrayexpress
Project description:BACKGROUND - IL-6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem cell transplantation (alloSCT) and is an attractive therapeutic target. METHODS - A registered phase I/II study (ACTRN12612000726853) of IL-6 receptor (IL-6R) neutralizing antibody administration on day -1 to patients receiving full or reduced-intensity conditioning (RIC) and alloSCT from HLA-matched sibling or unrelated donors with standard cyclosporin and methotrexate GVHD prophylaxis. The primary endpoint was incidence of grade II-IV acute GVHD. Outcomes were compared to a non-randomized but contemporaneous group of study patients receiving the same alloSCT in the absence of IL-6R mAb. FINDINGS - Cytokine and pharmacokinetic analysis confirmed transient IL-6 dysregulation in the first month after alloSCT with complete inhibition following IL-6R mAb administration. With median follow up of 497 days, the incidence of grade II-IV GVHD was 12.5% in recipients of IL-6R inhibition (n = 48) versus 41.5% in the (n = 53) control cohort (P = 0.001). Low rates of acute GVHD were noted in patients receiving IL-6R inhibition relative to control patients following both myeloablative (12.5% vs. 46.4%, P = 0.03) and RIC (12.5% vs. 36.0%, P = 0.04). The incidence of severe (grade III/IV) acute GVHD was 4.2% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.012). Relapse and chronic GVHD were unchanged. Immune reconstitution was preserved in recipients of IL-6R inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION - IL-6 is the principal detectable and dysregulated cytokine secreted after alloSCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution and a sustained graft-versus-leukemia effect. Single colour, Illumina Human HT12v4 Beadarrays.
2014-09-09 | E-GEOD-61201 | biostudies-arrayexpress
Project description:Scleroderma is an autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy and fibrosis. We have previously demonstrated that low Fli1 expression in scleroderma fibroblasts and endothelial cells plays an important role in SSc pathogenesis. Cells of myeloid and lymphoid origin also express Fli1 and are dysregulated in patients with SSc, playing key roles in disease pathogenesis However, a role for immune Fli1 in SSc has not yet been described. Our aim was to elucidate whether Fli1 contributes to the immune dysregulation seen in scleroderma. Comparison of the expression of Fli1 in monocytes, B- and T-cell fractions of PBMCs isolated from scleroderma patients and healthy controls, showed an increase in Fli1 levels in monocytes. We used siRNA transfected human myeloid cells and mouse peritoneal macrophages obtained from Fli1flox/floxLysMCre+/+ mice, and found that markers of alternative macrophage activation were increased with Fli1 deletion. Coculture of Fli1-deficient myeloid cells and primary human or mouse fibroblasts resulted in a potent induction of collagen type I, independent of TGFβ upregulation. We next analyzed global gene expression profile in response to Fli1 downregulation, to gain further insight into the molecular mechanisms of this process and to identify differentially expressed genes in myeloid cells. Of relevance to SSc, the top most upregulated pathways were hallmark IFN-ɣ and IFN-α response. Additionally, several genes previously linked to SSc pathogenesis and fibrosis in general were also induced, including MCP-1, MCP-3, MMP12, and CXCL10. ANKRD1, a profibrotic transcription co-regulator was the top upregulated gene in our array. Our results show that Fli1-deficient myeloid cells share key features with cells from SSc patients, with higher expression of profibrotic markers and activation of interferon responsive genes, thus suggesting that low Fli1 may contribute to SSc pathogenesis.
2020-06-09 | GSE144625 | GEO