Dataset Information

IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.

ABSTRACT: Treg therapies are being tested in clinical trials in transplantation and autoimmune diseases, however, the impact of inflammation on Tregs remains controversial. We challenged human Tregs ex-vivo with pro-inflammatory cytokines IL-6 and TNFα and observed greatly enhanced proliferation stimulated by anti-CD3 and anti-CD28 (aCD3/28) beads or CD28 superagonist (CD28SA). The cytokine-exposed Tregs maintained high expression of FOXP3 and HELIOS, demethylated FOXP3 enhancer, and low IFNγ, IL-4, and IL-17 secretion. Blocking TNF receptor using etanercept or deletion of TNF receptor 2 using CRISPR/Cas9 blunted Treg proliferation and attenuated FOXP3 and HELIOS expression. These results prompted us to consider using CD28SA together with IL-6 and TNFα without aCD3/28 beads (beadless) as an alternative protocol for therapeutic Treg manufacturing. Metabolomics profiling revealed more active glycolysis and oxidative phosphorylation, increased energy production, and higher antioxidant potential during beadless Treg expansion. Finally, beadless expanded Tregs maintained suppressive functions in vitro and in vivo. These results demonstrate that human Tregs positively respond to proinflammatory cytokines with enhanced proliferation without compromising their lineage identity or function. This property can be harnessed for therapeutic Treg manufacturing.

SUBMITTER: Skartsis N

PROVIDER: S-EPMC8732758 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.

Skartsis Nikolaos N Peng Yani Y Ferreira Leonardo M R LMR Nguyen Vinh V Ronin Emilie E Muller Yannick D YD Vincenti Flavio F Tang Qizhi Q

Frontiers in immunology 20211223

Treg therapies are being tested in clinical trials in transplantation and autoimmune diseases, however, the impact of inflammation on Tregs remains controversial. We challenged human Tregs <i>ex-vivo</i> with pro-inflammatory cytokines IL-6 and TNF<i>α</i> and observed greatly enhanced proliferation stimulated by anti-CD3 and anti-CD28 (aCD3/28) beads or CD28 superagonist (CD28SA). The cytokine-exposed Tregs maintained high expression of FOXP3 and HELIOS, demethylated FOXP3 enhancer, and low IFN ...[more]

PMID: 35003100

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Project description:BackgroundIn vasovasostomy (VV) surgery, the micro-surgical technique has consistently been shown to provide superior outcomes to both macroscopic and loupe-assisted techniques, with large studies showing overall patency rates of ~86% and pregnancy rates of ~52%. However, the question of whether a single- or double-layer anastomosis offers the best outcomes remains contentious, and despite the popularity of the two-layer technique, a meta-analysis suggests little difference in outcomes. This study records the outcomes of a single-surgeon series of a simplified single-layer technique, along with the comparative outcomes and predictive factors.MethodsA retrospective analysis of 237 consecutive patients undergoing microsurgical vasectomy reversal between 2010 and 2022 in a single institution was performed. A microsurgical, single-layer, six-point, 8-0 nylon anastomosis was performed with macroscopic intra-operative assessment of vasal fluid. An ipsilateral vasoepididymostomy (VE) was only performed in cases of complete absence of vasal fluid or the presence of toothpaste-like discharge (bilateral VE were excluded from this series). Semen analysis was performed 3 months postoperatively to assess for the presence of motile sperm.ResultsA total of 237 men underwent microsurgical vasectomy reversal over a 12-year period. The median age of men at vasectomy was 34 years. The median age at vasectomy reversal was 42 years. The median obstructive interval was 7.3 years. An overall patency rate of 85.8% was achieved (motile sperm present), with 53.8% having a sperm count greater than 15 million/mL on initial 3-month assessment. For obstructive intervals of <3, 3-8, 9-14, and ≥15 years, there were declining patency rates of 96.3%, 90.5%, 80.0%, and 74.1%, respectively (P=0.04). These are the equivalent outcomes to published high-volume two-layer studies. We found no difference between patency rates of VV performed on the straight vas vs. the convoluted vas, and no difference when only one side could be re-anastomosed (20 patients).ConclusionsUsing a micro-surgical technique in high volume, similar outcomes can be achieved from a simplified single-layer VV technique with fewer sutures, as compared to the more complex two-layer techniques described. We postulate that this may be due to reduced ischaemia relating to fewer sutures and less tissue-handling. Given the associated time and cost savings, as well as the easier learning curve involved, we would advocate the use of this technique in routine VV practise.

Dataset Information

IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.

Publications

IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.

Similar Datasets

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