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Maintenance of beta cell function in adolescent T1D subjects treated with a single dose of polyclonal expanded Treg is linked to lower ex vivo Treg expansion

ABSTRACT: Maintenance of beta cell function in adolescent T1D subjects treated with a single dose of polyclonal expanded Treg is linked to lower ex vivo Treg expansion

PROVIDER: PRJNA1017390 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26060433.fastq.gz	Fastqsanger.gz
	SRR26060434.fastq.gz	Fastqsanger.gz
	SRR26060435.fastq.gz	Fastqsanger.gz
	SRR26060436.fastq.gz	Fastqsanger.gz
	SRR26060437.fastq.gz	Fastqsanger.gz

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Maintenance of beta cell function in adolescent T1D subjects treated with a single dose of polyclonal expanded Treg is linked to lower ex vivo Treg expansion

Project description:Adoptive transfer of CD4+CD25hiCD127low FOXP3+ regulatory T cells (Treg) improves outcome as an adjunct treatment in transplantation to maintain tolerance. Phase I clinical trials have shown safety in adults, however, adoptive Treg tolerance is poorly understood in autoimmunity. Here, we explore factors contributing to efficacy in an autologous polyclonal expanded Treg (expTregs) Phase 2 clinical trial in 107 adolescents with recent-onset T1D (Sanford/Lisata Therapeutics Trex Phase 2 clinical trial) randomized 1:1:1 high and low treatment to placebo. A single dose of expTreg therapy (1-24x106cells/kg) did not prevent the decline in the residual beta cell function over two years compared to placebo (p=0.39), regardless of age, baseline c-peptide, or dose of expTreg (p=0.27). expTregs were a highly activated, pure, and suppressive Treg population as determined using flow cytometry and bulk RNA-seq prior to adoptive transfer. A transient increase of activated memory Tregs was detectable by flow cytometry and single-cell RNA-seq one week after infusion in the high dose cohort (p=0.003), suggesting effective transfer of expTreg. However, lower in vitro fold expansion and its linked gene signature associated with better outcome regardless of Treg dose. Together, these results suggest that expTregs quantity alone does not alter outcome; instead, expTreg quality, likely influenced by endogenous Treg features, may be important factors contributing to the efficacy of this treatment in preventing T1D progression.

2024-04-15 | GSE243201 | GEO

Expression data from recent-onset T1D patients and controls

2008-02-22 | GSE10586 | GEO

DRAK2 alters IL-2 sensitivity and Treg development

Project description:Drak2¬-deficient (Drak2-/-) mice are resistant to multiple models of autoimmunity, yet effectively eliminate pathogens and tumors. Thus, DRAK2 is an ideal target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic Treg development and by impacting the sensitivity of conventional T cells to Treg-mediated suppression.

2023-02-09 | PXD037922 | Pride

Transcription profiling of human FoxP3+CD4+CD25+high regulatory T cells (Tregs) isolated from recent-onset type 1 diabetes mellitus (T1D) patients and controls

Project description:Naturally occurring FoxP3+CD4+CD25+high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing auto-reactive CD4+CD25- T cell activity. Although Tregs from T1D subjects are functionally deficient, there is little knowledge of the molecular mechanisms that orchestrate this loss of Treg function. We observed increased apoptosis (by a novel YOPRO-1/7AAD dual staining protocol) and decreased suppression in polyclonal Tregs in the periphery from high at-risk and T1D subjects. We hypothesize that prior to and during the onset of disease, Tregs lack pro-survival signals and are caught up in a relatively deficient cytokine milieu whose effects may be detectable in the periphery. Microarray analysis was performed on un-stimulated Tregs from 12 subjects with newly diagnosed T1D and 15 healthy controls. Experiment Overall Design: Recent-onset T1D subjects were T1D patients diagnosed within 1 year. At the time of each visit, the following clinical measurements were taken: HbA1c, glucose level, height, weight and BMI. The presence of auto-antibodies was measured from peripheral blood. Peripheral blood mononuclear cells (PBMCs) were collected and Tregs were isolated using FACS isolation. RNA was isolated, amplified and cRNA was fragmented and hybridized to Affymetrix whole genome U133Plus2.0 arrays having 54675 probe-sets. Bayesian Hierarchical analysis (BGX) was used to analyze the data.

2008-04-07 | E-GEOD-10586 | biostudies-arrayexpress

Novel risk variants affecting enhancers of TH1 and TREG cells in type 1 diabetes [RNA-seq]

Project description:We generated expression profiles of TH1 and TREG cells from T1D and healthy subjects by RNA-Seq. By integrating RNA-Seq dta with other data sets, we predicted and validated serveral T1D risk SNPs.

2019-03-26 | GSE112341 | GEO

T1D

Project description:WTCCC1 project Type 1 Diabetes (T1D) samples

| EGAD00000000008 | EGA

T1D genotyping through SNP-array technology

Project description:T1D genotyping

| PRJEB78497 | ENA

Novel risk variants affecting enhancers of TH1 and TREG cells in type 1 diabetes [ChIP-seq]

Project description:Most type 1 diabets (T1D) associated SNPs are located in non-coding regions, making it hard to understand their functional impact. We performed epigenomic profiling of two enhancer marks, H3K4me1 and H3K27ac, using primary TH1 and TREG cells from healthy and T1D subjects. By integrating enhancers predicted using these ChIP-Seq data, T1D associated SNPs and additional supporting data, we found and validated several novel risk SNPs for T1D.

2019-03-26 | GSE112337 | GEO

10X genomics single cell GEX and VDJ 5' sequencing of PBMC from Type 1 Diabetes patients treated with Treg therapy alone or plus low dose IL-2

Project description:Background: A previous Phase I study showed that the infusion of autologous Treg cells expanded ex-vivo into recent onset Type 1 Diabetes (T1D) patients had an excellent safety profile, however, the majority of the infused Tregs could no longer be detected in the peripheral blood three months post-infusion (NCT01210664-Treg-T1D Trial). Interleukin-2 (IL-2) is a well-characterized cytokine that has been shown to enhance human Treg cell survival and expansion at low doses in vivo. Therefore, a Phase 1 study (NCT02772679-TILT trial) was conducted combining a single infusion of autologous polyclonal Tregs, expanded ex vivo, followed by one or two 5-day courses of recombinant human low dose IL-2 (ld-IL-2) at 0.3 x 10^6 to 1 x 10^6 units/dose. The infusions had an acceptable safety profile, but all 9 patients failed to maintain C-peptide production at pre-treatment levels. Results: Single cell gene expression analysis revealed that the combination therapy led to a transient increase in the number of infused and endogenous Tregs but also resulted in a significant increase from baseline in a subset of activated NK, Mucosal-associated invariant T (MAIT) and clonal CD8+ T populations from populations

2021-09-25 | GSE178991 | GEO

Sequential induction of effector function, tissue migration and cell death during polyclonal activation of regulatory T-cells

Project description:The ability of Treg-cells to produce interleukin-10 (IL-10) is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, only few Treg-cells produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregcells we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Treg-cells, which not only led to numeric expansion but also to a dramatic increase in IL- 10 production. IL-10 secreting Treg-cells strongly upregulated surface receptors associated with suppressive function, and had higher but IL-10 independent, in vitro suppressive capacity than nonproducing Treg-cells. Furthermore, polyclonally expanding Treg-cells shifted their migration receptor pattern after activation from a lymph node-seeking to an inflammation-seeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Treg-cells from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Treg-cells results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression. total samples analysed are 4

2013-08-10 | E-GEOD-41492 | biostudies-arrayexpress

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