The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn’s disease
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PROVIDER: PRJNA1200031 | ENA |
REPOSITORIES: ENA
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Project description:Background Treatment strategies for Crohn’s disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) is an emerging therapy for medically-refractory CD though the mechanisms through which it circumvents refractory pathophysiology are unknown. Objective The objective of this study is to understand how the immune system reconstitutes post-SCT and whether SCT may function as a cellular therapy restoring appropriately responsive immune cell populations from hematopoietic stem cells (HSCs). Design Adults with CD with active clinical and endoscopic disease who failed available medical therapies were enrolled in a Phase II study of SCT for refractory CD (n=19). Blood and intestinal samples were collected longitudinally and analyzed using CyTOF, scRNA-seq and TCRβ-seq. Stem cell autografts were functionally assayed in mouse xenograft models. Results scRNA-seq and CyTOF analyses reveal that SCT predominantly affected the intestinal myeloid lineage with loss of inflammatory populations and return of macrophages capable of supporting mucosal healing. Xenograft models using patient HSCs suggested HSCs support the early reconstitution of the myeloid lineage and reveal an impairment of short and long-term HSC engraftment that may determine SCT outcomes. Conclusions This study suggests SCT functions as a myeloid-directed cellular therapy reinforcing the critical role of macrophages in refractory CD pathophysiology and as a target for cellular therapies. Furthermore, we report an unrecognized functional heterogeneity among HSC subpopulations in CD that may be relevant to our understanding of CD treatment and pathophysiology.
2025-01-23 | GSE284677 | GEO
Project description:Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternatively-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balanced of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis and signaling pathway deconvolution. Our findings reveal that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way dependent on JNK signaling. We uncover principles of the selectively inhibition by TNF via the type 1 TNF receptor on specific populations of alternative activated macrophages.
2022-01-07 | PXD028667 | Pride
Project description:Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternatively-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balanced of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis and signaling pathway deconvolution. Our findings reveal that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way dependent on JNK signaling. We uncover principles of the selectively inhibition by TNF via the type 1 TNF receptor on specific populations of alternative activated macrophages.
2022-01-11 | GSE185378 | GEO
Project description:Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternatively-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balanced of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis and signaling pathway deconvolution. Our findings reveal that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way dependent on JNK signaling. We uncover principles of the selectively inhibition by TNF via the type 1 TNF receptor on specific populations of alternative activated macrophages.
2022-01-11 | GSE185375 | GEO
Project description:Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternatively-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balanced of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis and signaling pathway deconvolution. Our findings reveal that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way dependent on JNK signaling. We uncover principles of the selectively inhibition by TNF via the type 1 TNF receptor on specific populations of alternative activated macrophages.
2022-01-11 | GSE185376 | GEO
Project description:Crohn’s disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by transmural disease. The concept of transmural healing (TH) has been proposed as an indicator of deep clinical remission of CD and as a predictor of favorable treatment endpoints. Understanding the pathophysiology involved in transmural disease is critical to achieving these endpoints. How-ever, most studies have focused on the colon intestinal mucosa, overlooking the contribution of the colon intestinal wall in Crohn’s disease. Multi-omics approaches have provided new avenues for exploring the pathogenesis of Crohn’s disease and identifying potential biomarkers. Therefore, we analyzed and compared the gene and protein expression and dysregulated biological functions in the distinct tissue compartments of mucosa and submucosa/wall of colon resections from CD patients. We aimed to use transcriptomic and proteomic technologies to compare immune and mesenchymal cell profiles and pathways in the mucosal and submucosa/wall compartments to better understand refractory disease elements to achieve transmural healing. We employed a comprehensive multi-omics approach to investi-gate the molecular profiles of the colon mucosa and submucosa/wall compartments in patients with chronic Crohn’s disease. The results revealed similarities and differences in gene and protein ex-pression profiles, metabolic mechanisms, and immune and non-immune pathways between these two compartments. Additionally, the identification of protein isoforms highlights the complex molecular mechanisms underlying this disease. These findings have the potential to inform the development of novel therapeutic strategies to achieve TH.
2024-06-23 | PXD050335 | Pride
Project description:Treatment of severely refractory Crohn’s disease (CD) patients remains a clinical challenge. Recent studies show the efficacy of autologous hematopoietic stem cell transplant (HSCT) in these severely compromised patients. HSCT is thought to eliminate auto-reactive cells; however, no specific studies of immune reconstitution in CD patients are available. We studied a group of CD patients (n=18) receiving autologous HSCT and non-IBD patients (n=19) to elucidate the mechanism of interaction with the microorganisms.
2020-10-22 | GSE139179 | GEO
Project description:Treatment of severely refractory Crohn’s disease (CD) patients remains a clinical challenge. Recent studies show the efficacy of autologous hematopoietic stem cell transplant (HSCT) in these severely compromised patients. HSCT is thought to eliminate auto-reactive cells; however, no specific studies of immune reconstitution in CD patients are available. We studied a group of CD patients receiving autologous HSCT, with 50% of them achieving endoscopic drug-free remission. To elucidate the mechanism driving efficacy, we studied changes in the immune cell composition in tissue induced by HSCT.
2019-01-23 | GSE115390 | GEO
Project description:Broad-spectrum antibiotics are frequently prescribed to children. The period of early-childhood represents a time where the developing microbiota may be more sensitive to environmental perturbations, which thus might have long-lasting host consequences. We hypothesized that even a single early-life broad-spectrum antibiotic course at a therapeutic dose (PAT) leads to durable alterations in both the gut microbiota and host immunity. In C57BL/6 mice, a single early-life tylosin (macrolide) course markedly altered the intestinal microbiome, and affected specific intestinal T-cell populations and secretory IgA expression, but PAT-exposed adult dams had minimal immunologic alterations. No immunological effects were detected in PAT-exposed germ-free animals; indicating that microbiota are required for the observed activities. Together these results indicate the impact of a single therapeutic early-life antibiotic course altering the microbiota and modulating host immune phenotypes that persist long after exposure has ceased.
2017-09-19 | E-MTAB-5101 | biostudies-arrayexpress
Project description:Fibrostenotic disease is a common complication in Crohn’s disease (CD). We performed bulk RNA sequencing (n=16) of paired intestinal biopsies taken from nonstenotic and stenotic areas of patients with CD (n=8).
2023-04-26 | E-MTAB-12788 | biostudies-arrayexpress