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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

ABSTRACT: Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

PROVIDER: PRJNA934866 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23455086_1.fastq.gz	Fastqsanger.gz
	SRR23455086_2.fastq.gz	Fastqsanger.gz
	SRR23455087_1.fastq.gz	Fastqsanger.gz
	SRR23455087_2.fastq.gz	Fastqsanger.gz
	SRR23455088_1.fastq.gz	Fastqsanger.gz

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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

Project description:Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

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RNAseq on PBMC of three patients with Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL5) and three age and sex-matched controls

Project description:RNAseq on PBMC of three patients with Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL5) and three age and sex-matched controls.

2020-03-31 | E-MTAB-8875 | biostudies-arrayexpress

Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [TCR]

Project description:Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [TCR]

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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [Amplicon]

Project description:Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [Amplicon]

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Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model

Project description:Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene, which result in impaired processing of cytotoxic vesicles and hence compromised T and NK cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show 30-40% mortality. As a first step to meet this medical need, we developed and tested a curative genome editing strategy in the FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site (cSD) in Unc13d intron 26 and develop the clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV). Here, we employed CRISPR-Cas technology to delete the disease-underlying mutation in HSCs, and transplanted the Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Genotyping, phenotyping and CAST-Seq based off-target analyses of cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wildtype cells were comparable. LCMV challenge of the transplanted mice resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, while Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH. In sum, our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T cell response in the absence of genotoxicity-associated clonal outgrowth or leukemogenesis.

2023-07-04 | GSE225269 | GEO

Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [Amplicon]

2023-07-04 | GSE225540 | GEO

Gene Editing of Hematopoietic Stem Cells Restores T Cell Response in a Familial Hemophagocytic Lymphohistiocytosis Model [TCR]

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Murine Model of Familial Hemophagocytic Lymphohistiocytosis Hepatitis is Mediated by IFN-γ in a Predominantly Hepatic-Intrinsic Manner

Project description:Interferon gamma (IFN-γ) is the main cytokine driving Familial Hemophagocytic Lymphohistiocytosis (FHL) organ dysfunction. Hepatocytes are known to have IFN-γ receptor (IFN-γ-R). Blockade of IFN-γ pathway ameliorates FHL hepatitis, in animal models and in humans. However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. We report that IFN-γ-mediated hepatic injury in the murine model of FHL is caused by direct effect on the liver and has a necessary role in recruitment of the inflammatory mediators of injury in FHL: inflammatory monocytes and CD8+ effector memory T lymphocytes (CD8+ CD44hi CD62Llo) (Tem).

2022-06-02 | GSE168086 | GEO

Gene Expression Profiling of Peripheral Blood Mononuclear Cells from Children With Active Hemophagocytic Lymphohistiocytosis

Project description:Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed. In order to advance the understanding of FHL, we performed gene expression profiling of peripheral blood mononuclear cells (PBMCs) from 11 children with untreated FHL. Total RNA was isolated and gene expression levels were determined using microarray analysis. Comparisons between patients with FHL and normal pediatric controls (n = 30) identified 915 down-regulated and 550 up-regulated genes with 2.5-fold difference in expression (P = 0.05). The expression of genes associated with natural killer cell functions, innate and adaptive immune responses, pro-apoptotic proteins, and B- and T-cell differentiation were down-regulated in patients with FHL. Genes associated with the canonical pathways of IL-6, IL-10 IL-1, IL-8, TREM1, LXR/RXR activation, and PPAR signaling and genes encoding of anti-apoptotic proteins were overexpressed in patients with FHL. This, first study of genome-wide expression profiling in children with FHL demonstrates the complexity of gene expression patterns, which underly the immunobiology of FHL. 11 Patients and 33 controls

2011-12-12 | E-GEOD-26050 | biostudies-arrayexpress

Gene Expression Profiling of Peripheral Blood Mononuclear Cells from Children With Active Hemophagocytic Lymphohistiocytosis

2011-12-12 | GSE26050 | GEO