Myeloablation followed by autologous stem cell transplantation normalizes systemic sclerosis molecular signatures
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PROVIDER: PRJNA542097 | ENA |
REPOSITORIES: ENA
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Project description:This is global gene expression study of whole blood samples collected in the Cyclophosphamide Or Transplantation (SCOT) randomized controlled trial, as well as unaffected controls. Patients with diffuse cutaneous systemic sclerosis (scleroderma) received either myeloablation followed by autologous stem cell transplantation or intravenous cyclophosphamide
2019-07-10 | GSE130953 | GEO
Project description:OBJECTIVE:In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS:Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS:At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26?months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION:HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.
| S-EPMC7167108 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS. Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1x10^6 cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects. Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients.
2024-10-17 | PXD053129 | Pride
Project description:The SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial demonstrated clinical benefit of autologous hematopoietic stem cell transplant (HSCT) compared to cyclophosphamide (CYC) in scleroderma. We analyzed gene expression from peripheral blood mononuclear cells (PBMCs) of SCOT participants to identify those with differential treatment response.
2020-07-01 | GSE134310 | GEO
Project description:Localized scleroderma (LoS), or morphea, refers to a group of rare autoimmune connective tissue diseases. Autologous fat grafting was able to correct volume loss in patients with LoS to improve facial disfigurement.However, whether it could exert a positive effect on reversing skin sclerosis remains unclear.
2023-11-20 | GSE247804 | GEO
Project description:BackgroundSystemic sclerosis (SSc) patients often need immunosuppressive medication (IS) for disease control. If SSc is progressive despite IS, autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for selected SSc patients. aHSCT is effective with good available evidence, but not all patients achieve a treatment-free remission after aHSCT. Thus far, data about the need of IS after aHSCT in SSc is not published. The aim of this study was to investigate the use of IS after aHSCT, its efficacy, and the occurrence of severe adverse events (SAEs).MethodsTwenty-seven patients with SSc who had undergone aHSCT were included in this single-center retrospective cohort study. Clinical data, including IS, SAEs, and lung function data, were collected.ResultsSixteen of 27 (59.3%) patients received IS after aHSCT. Methotrexate, rituximab, mycophenolate, cyclophosphamide, and hydroxychloroquine were most commonly used. The main reason for starting IS was SSc progress. Nine patients received rituximab after aHSCT and showed an improvement in modified Rodnan skin score and a stabilization of lung function 2 years after rituximab. SAEs in patients with IS after aHSCT (50.0%) were not more common than in patients without IS (54.6%). SAEs were mostly due to SSc progress, secondary autoimmune diseases, or infections. Two deaths after aHSCT were transplantation related and three during long-term follow-up due to pulmonary arterial hypertension.ConclusionDisease progression and secondary autoimmune diseases may necessitate IS after aHSCT in SSc. Rituximab seems to be an efficacious treatment option in this setting. Long-term data on the safety of aHSCT is reassuring.
| S-EPMC8801940 | biostudies-literature
Project description:Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results.
| S-EPMC9266677 | biostudies-literature
Project description:Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) is a potential treatment for patients suffering from aggressive multiple sclerosis (MS). However it remains unresolved whether autologous CD34+ hematopoietic progenitor cells of MS patients show gene expression differences prior to aHSCT that indicate a preset proinflammatory state, which would then also predispose to or predetermine recurrence of the autoimmune disease. To approach this key point we compared the micro RNA gene expression signature of CD34+ cells collected from MS patients and healthy donors (HD). Gene expression of CD34+ cells was analysed with the Human miRNA Microarray (Agilent-Technologies) chip. No substantial alterations in the gene expression profile of CD34+ HPCs in MS were observed.
2012-09-05 | GSE27690 | GEO
Project description:Multiple sclerosis is an immune mediated disease of the central nervous system. High-dose immunosuppression therapy followed by autologous hematopoietic stem cell transplantation (HDI/AHSCT) has emerged in the past few years as a new treatment strategy in patients with severe MS and refractory to conventional treatment. We characterized the molecular profile of T cells during immune reconstitution of these patients. Total RNA of CD4+ and CD8+ T cells from eight MS patients before transplantation and four patients at 6 months, 1 and 2 years after transplantation was processed for DNA microarray analysis. We investigated the molecular and biological function of DEG using bioinformatics tools and selected genes involved with immune response to measure quantitative gene expression by Real-time PCR. In CD8+ T cells, we measured the levels of expression of 23 genes modulated after transplantation: nine transcriptional factors (LEF1, FOXD1, CEBPD, JUN, JUNB, RELB, IFI16, AEBP1) including the translational factor PDCD4, the chemokine CCR7 and adhesion molecule L Selectin, three TNF superfamily members (TNFRSF4, TNFRSF19L, LT?), seven genes involved with molecular signaling (SOCS1, SOCS3, DGKH, CSNK1L1, IKB?, IKB?, IKB?), and the immune cell receptors CD47 and SIRPG. In CD4+ T cells, we evaluated the relative level of expression of STAT3, FcRL3, PDCD1, DGKH, CSNK1L1, L Selectin, CCR7 and PIAS3 that were all modulated after transplantation. We found significantly transcriptional changes in both T cells subsets during the first 2 years post-transplantation, but the analysis of CD8+ T cells revealed more extensive changes of genes involved in effector immune responses. In order to study the transcriptional changes in T cell subsets from MS patients submitted HID/HSCT, immunomagnetically purified CD4+ and CD8+ T-cells from the peripheral blood of 8 patients before transplantation and 4 patients 6 months, 1 year and 2 years after tranplantation, as well as from 4 healthy controls were isolated and processed the microarray assay according Agilent's protocol. The differential expressed genes, molecular characterization and networks analysis were evaluated using robust bioinformatic tools, then the real time PCR was done to validate the 27 immune related-genes.
2011-11-03 | E-GEOD-32988 | biostudies-arrayexpress
Project description:Systemic sclerosis is a connective tissue disease affecting skin and internal organs, characterized by a triad of inflammation, vasculopathy and progressive fibrosis, due to deposition of mainly type I collagen. Out of the intricate mechanisms involved in the pathogenesis of the disease, evidence indicates that TGFbeta signaling plays a central role in mediating the effects of several pro-fibrotic effectors. In addition, TGFbeta is induced by hypoxia in cultured fibroblasts, an observation suggesting a role for this cytokine in linking vasculopathy and fibrosis in the disease. Not surprisingly, TGFbeta and Wnt signaling are among the most prevalent pathways found in global gene expression studies performed on systemic sclerosis skin biopsies. In this perspective, modulation of TGFbeta activity remains a top therapeutic target in systemic sclerosis drug development. We recently performed whole-body magnetic resonance imaging (MRI) studies in systemic sclerosis patients, and evidenced deep connective tissue infiltrates surrounding tendons in patients with active disease, and tendon friction rubs. Tenosynovitis and arthritis were also found by MRI in one third of the patients. We performed tenosynovial biopsies in patients with clinically active tenosynovitis, in order to evaluate whether such samples would provide additional information on disease mechanisms. Here, we report that these samples are characterized by the over-expression of genes involved in fibrosis, TGFbeta/Wnt signaling, chemokines and cytokines, but also by the concurrent over-expression of several ubiquitin-specific peptidases (USPs). Among the USPs overexpressed in systemic sclerosis tenosynovial biopsies, USP15 is known to specifically deubiquitinate SMAD3, and the TGFbeta Receptor 1. These results triggered us to perform additional experiments in order to test whether USP15 overexpression plays a role in the pathogenesis of systemic sclerosis via decreased ubiquitin-mediated degradation of proteins involved in TGFbeta signaling.
2017-06-30 | GSE93698 | GEO