Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease [IL-17]
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PROVIDER: PRJNA1212730 | ENA |
REPOSITORIES: ENA
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Project description:Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutics agents targeting dysregulated cytokines including IL-17 and CSF-1 have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent FDA approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the US, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single cell sequencing-based approaches in our informative preclinical cGVHD models to “reverse engineer” temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, non-intuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocytes within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 post-HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and non-responders to relevant therapeutics targeting these pathways.
2025-06-01 | GSE287419 | GEO
Project description:Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutics agents targeting dysregulated cytokines including IL-17 and CSF-1 have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent FDA approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the US, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single cell sequencing-based approaches in our informative preclinical cGVHD models to “reverse engineer” temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, non-intuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocytes within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 post-HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and non-responders to relevant therapeutics targeting these pathways.
2025-06-01 | GSE287415 | GEO
Project description:Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease [CSF-1]
| PRJNA1212725 | ENA
Project description:Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutics agents targeting dysregulated cytokines including IL-17 and CSF-1 have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent FDA approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the US, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single cell sequencing-based approaches in our informative preclinical cGVHD models to “reverse engineer” temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, non-intuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocytes within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 post-HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and non-responders to relevant therapeutics targeting these pathways.
2025-06-01 | GSE287420 | GEO
Project description:Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease [Naïve]
| PRJNA1212729 | ENA
Project description:IL-1beta activates IL-17 via calcium
| PRJNA484807 | ENA
Project description:Background: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that CEBPβ, the transcription factor regulating IL-17-responsive genes, is expressed in differentiated KCs. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist. RHE samples were treated with IFNg, IL-22 and IL-17 and compared with control
2014-02-28 | E-GEOD-52361 | biostudies-arrayexpress
Project description:The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the haematopoietic or non-haematopoietic compartments were wild-type (WT), IL-10–/–, G-CSFR–/– or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after with G-CSF mobilization required direct signalling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4+CD25+ regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell’s ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.
2014-02-03 | E-GEOD-54616 | biostudies-arrayexpress
Project description:IL-17 mediates immune protection from fungi and bacteria as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of LUBAC as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.
2020-07-15 | PXD019020 | Pride
Project description:Il-17 p53 Developmental Series
| PRJNA953010 | ENA