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https://www.readbyqxmd.com/read/29913309/the-causes-and-consequences-of-variation-in-human-cytokine-production-in-health
#1
REVIEW
Melanie Schirmer, Vinod Kumar, Mihai G Netea, Ramnik J Xavier
Cytokines are important cell-signaling molecules that activate and modulate immune responses. Major factors influencing cytokine variation in healthy individuals are host genetics, non-heritable factors and the microbiome. Genetic variation accounts for a significant part of heterogeneity in cytokine production by peripheral blood mononuclear cells. Variation in cytokines such as IL-6 and IL-6Ra is strongly influenced by heritability, suggesting an evolutionarily pressure for their genetic regulation that potentially contributes to differences in immune responsiveness between human populations...
June 15, 2018: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29913182/the-genetic-architecture-of-type-1-diabetes-mellitus
#2
REVIEW
Denis M Nyaga, Mark H Vickers, Craig Jefferies, Jo K Perry, Justin M O'Sullivan
Type 1 diabetes mellitus (T1D) is a complex autoimmune disorder characterised by loss of the insulin-producing pancreatic beta cells in genetically predisposed individuals, ultimately resulting in insulin deficiency and hyperglycaemia. T1D is most common among children and young adults, and the incidence is on the rise across the world. The aetiology of T1D is hypothesized to involve genetic and environmental factors that result in the T-cell mediated destruction of pancreatic beta cells. There is a strong genetic risk to T1D; with genome-wide association studies (GWAS) identifying over 60 susceptibility regions within the human genome which are marked by single nucleotide polymorphisms (SNPs)...
June 15, 2018: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29913039/regulatory-t-cells-from-allo-to-xenotransplantation-opportunities-and-challenges
#3
REVIEW
Mohamed B Ezzelarab
Regulatory T cells (Treg) are currently being evaluated in clinical allotransplantation for tolerance induction, with proven safety in humans with autoimmune diseases and graft-versus-host disease. A considerable amount of recent data suggests that additional factors may need to be validated, including the stability and commitment of newly discovered Treg subsets under inflammatory conditions, to further warrant safe and effective Treg-based therapeutic approaches. This review explores the opportunities and challenges of Treg-based cell therapy in xenotransplantation...
May 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29912461/exploiting-crispr-cas9-technology-to-investigate-individual-histone-modifications
#4
Juan-José Vasquez, Carolin Wedel, Raul O Cosentino, T Nicolai Siegel
Despite their importance for most DNA-templated processes, the function of individual histone modifications has remained largely unknown because in vivo mutational analyses are lacking. The reason for this is that histone genes are encoded by multigene families and that tools to simultaneously edit multiple genomic loci with high efficiency are only now becoming available. To overcome these challenges, we have taken advantage of the power of CRISPR-Cas9 for precise genome editing and of the fact that most DNA repair in the protozoan parasite Trypanosoma brucei occurs via homologous recombination...
June 15, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29912401/challenges-to-reshape-the-future-of-type-1-diabetes-research
#5
David Bleich, David H Wagner
Context: Immunotherapy trials to prevent type 1 diabetes have been unsuccessful for more than fifteen years. Understanding pitfalls and knowledge gaps in the immunology of type 1 diabetes should lead us in new directions that will yield better trial outcomes. A proposal is made for precision medicine trial design in future type 1 diabetes studies. Evidence Acquisition: High quality peer-reviewed basic science and clinical research trials for type 1 diabetes were used in this Perspectives article...
June 14, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29912283/immune-evasive-gene-switch-enables-regulated-delivery-of-chondroitinase-after-spinal-cord-injury
#6
Emily R Burnside, Fred De Winter, Athanasios Didangelos, Nicholas D James, Elena-Cristina Andreica, Hugo Layard-Horsfall, Elizabeth M Muir, Joost Verhaagen, Elizabeth J Bradbury
Chondroitinase ABC is a promising preclinical therapy that promotes functional neuroplasticity after CNS injury by degrading extracellular matrix inhibitors. Efficient delivery of chondroitinase ABC to the injured mammalian spinal cord can be achieved by viral vector transgene delivery. This approach dramatically modulates injury pathology and restores sensorimotor functions. However, clinical development of this therapy is limited by a lack of ability to exert control over chondroitinase gene expression. Prior experimental gene regulation platforms are likely to be incompatible with the non-resolving adaptive immune response known to occur following spinal cord injury...
June 14, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29910815/-toxoplasma-chinese-1-strain-of-wh3%C3%AE-rop16-i-iii-gra15-ii-genetic-background-contributes-to-abnormal-pregnant-outcomes-in-murine-model
#7
Cong Wang, Weisheng Cheng, Qian Yu, Tian Xing, Shoubin Chen, Lei Liu, Li Yu, Jian Du, Qingli Luo, Jilong Shen, Yuanhong Xu
Toxoplasma gondii infection evokes a strong Th1-type response with interleukin (IL)-12 and interferon (IFN)-γ secretion. Recent studies suggest that the infection of pregnant mice with T. gondii may lead to adverse pregnancy results caused by subversion of physiological immune tolerance at maternofetal interface rather than direct invasion of the parasite. Genotype-associated dense granule protein GRA15II tends to induce classically activated macrophage (M1) differentiation and subsequently activating NK, Th1, and Th17 cells whereas rhoptry protein ROP16I/III drives macrophages to alternatively activated macrophage (M2) polarization and elicits Th2 immune response...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29910806/targeting-the-epidermal-growth-factor-receptor-can-counteract-the-inhibition-of-natural-killer-cell-function-exerted-by-colorectal-tumor-associated-fibroblasts
#8
Delfina Costa, Roberta Venè, Roberto Benelli, Emanuele Romairone, Stefano Scabini, Silvia Catellani, Barbara Rebesco, Luca Mastracci, Federica Grillo, Simona Minghelli, Fabrizio Loiacono, Maria Raffaella Zocchi, Alessandro Poggi
Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29910670/icos-signal-facilitates-foxp3-transcription-to-favor-suppressive-function-of-regulatory-t-cells
#9
Qianmei Chen, Lijun Mo, Xiangsheng Cai, Lili Wei, Zhengneng Xie, Hongwei Li, Jinlong Li, Zhiming Hu
Inducible costimulator (ICOS) plays an important role in the suppressive immunity mediated by regulatory T cells (Tregs), but the molecular regulation mechanism is not well known. Here we performed a study to explore the possible mechanism by which ICOS regulates the suppressive functions and survival of Tregs. This study showed that both the ICOS and CD28 signal could promote the survival of Tregs. However, ICOS but not CD28 improved the suppressive function of Tregs. Mechanistic studies demonstrated that ICOS could induce the transcription activity of Foxp3, by facilitating the nuclear factor of activated T cells (NFAT): Foxp3 over NFAT: activator protein 1 (AP-1)...
2018: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/29910042/belimumab-in-kidney-transplantation-an-experimental-medicine-randomised-placebo-controlled-phase-2-trial
#10
Gemma D Banham, Shaun M Flint, Nicholas Torpey, Paul A Lyons, Don N Shanahan, Adele Gibson, Christopher J E Watson, Ann-Marie O'Sullivan, Joseph A Chadwick, Katie E Foster, Rachel B Jones, Luke R Devey, Anna Richards, Lars-Peter Erwig, Caroline O Savage, Kenneth G C Smith, Robert B Henderson, Menna R Clatworthy
BACKGROUND: B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients...
June 14, 2018: Lancet
https://www.readbyqxmd.com/read/29909913/gmp-car-t-cell-production
#11
REVIEW
Adrian P Gee
The clinical success achieved using CD19-directed CAR-T cells has stimulated many academic institutions to explore the feasibility of manufacturing these, and other CAR-T cells, in-house. This article reviews the issues that must be addressed in order to achieve this goal. It includes the manufacturing infrastructure, the regulatory environment, practical aspects of production, and the costs involved.
June 2018: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29909367/regulatory-t-cell-subsets-are-differentially-dependent-on-cd28-for-their-proliferation
#12
Ei Wakamatsu, Hiroki Omori, Shizuka Ohtsuka, Shuhei Ogawa, Jonathan M Green, Ryo Abe
It is thought that CD28 plays a crucial role in the maintenance of regulatory T cell (Treg) pool size through promoting the development and proliferation of these cells. However, recently we found that the dependency on CD28 co-stimulation for their development is different between Treg subsets, thymus-derived Tregs (tTregs, CD28-dependent) and peripherally-derived Tregs (pTregs, CD28-independent), suggesting that CD28 may also have differential influences on the homeostasis of each Treg subset. Here, we demonstrated that both Treg subsets were reduced in secondary lymphoid organs of CD28 deficient mice, and that this reduction was due to impaired proliferation in both Treg subsets by the intrinsic CD28 defect...
June 14, 2018: Molecular Immunology
https://www.readbyqxmd.com/read/29909346/kuijieling-regulates-the-differentiation-of-treg-and-th17-cells-to-ameliorate-experimental-colitis-in-rats
#13
Yu Long, Sixin Li, Jingchun Qin, Liwei Xie, Liping Gan, Fengming Jie, Yanli Wu, Yanwu Li, Qun Du
BACKGROUND: Regulatory T (Treg) cells and T helper 17 (Th17) cells play crucial roles in ulcerative colitis (UC). Kuijieling (KJL) is an effective Chinese medicine formula for treating UC in clinic. Kuijieling has shown remedy effect on the imbalance between Treg and Th17 cells. This study aimed to further reveal the exact underlying mechanism of how Kuijieling regulates the differentiation of Treg and Th17 cells in the treatment of UC. METHODS: Colitis was induced by trinitrobenzene sulfonic acid in rats and treated by KJL...
June 14, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29909290/induction-of-redd1-via-ap-1-prevents-oxidative-stress-mediated-injury-in-hepatocytes
#14
Sam Seok Cho, Kyu Min Kim, Ji Hye Yang, Ji Young Kim, Su Jung Park, Seung Jung Kim, Jae Kwang Kim, Il Je Cho, Sung Hwan Ki
Regulated in development and DNA damage responses 1 (REDD1) is an inducible gene in response to various stresses, which functions as a negative regulator of the mammalian target of rapamycin protein kinase in complex 1. In the present study, we identified the role of REDD1 under the oxidative stress-mediated hepatocyte injury and its regulatory mechanism. REDD1 protein was increased in H2 O2 or tert-butylhydroperoxide (t-BHP)-treated hepatocytes. H2 O2 also elevated REDD1 mRNA levels. This event was inhibited by antioxidants such as diphenyleneiodonium chloride, N-acetyl-L-cysteine, or butylated hydroxy anisole...
June 14, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29909233/phenotype-analyses-of-il-10-producing-foxp3-cd4-t-cells-increased-by-subcutaneous-immunotherapy-in-allergic-airway-inflammation
#15
Masaya Matsuda, Yuki Morie, Hirotaka Oze, Kana Doi, Tatsuya Tsutsumi, Junpei Hamaguchi, Miki Inaba, Takeshi Nabe
INTRODUCTION: The mechanisms of allergen immunotherapy are not fully elucidated. Here, we sought to develop a murine model to demonstrate the effectiveness of subcutaneous immunotherapy (SCIT) for allergic responses. As excessive antigen dosages may induce immune tolerance in sensitized mice, the effects of SCIT were assessed by varying the antigen dosage. The mechanisms of SCIT were analyzed by focusing on the induction of Foxp3+ Treg cells and IL-10-producing Foxp3- CD4+ T cells, as well as on the phenotype of the latter cells...
June 14, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29908119/cd4-foxp3-regulatory-t-cell-mediated-immunomodulation-by-anti-depressants-inhibiting-acid-sphingomyelinase
#16
Jürgen Schneider-Schaulies, Niklas Beyersdorf
Acid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+ Foxp3+ regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+ T (Tconv) cells. In ASM-deficient (Smpd1-/-) as compared to wt mice, membranes of T cells contain 7-10-fold more sphingomyelin and 2-3-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation...
June 1, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29908067/effects-of-type-i-interferons-in-malaria
#17
REVIEW
Ismail Sebina, Ashraful Haque
Type I interferons are a family of cytokines with a wide range of biological activities including anti-viral and immune-regulatory functions. Here, we focus on the protozoan parasitic disease, malaria, and examine the effects of type I IFN-signalling during Plasmodium infection of humans and experimental mice. Since the 1960's, there have been many studies in this area, but a simple explanation for the role of type I IFN has not emerged. Although epidemiological data are consistent with roles for type I IFN in influencing malaria disease severity, functional proof of this remains sparse in humans...
June 16, 2018: Immunology
https://www.readbyqxmd.com/read/29907673/role-of-mir-98-and-its-underlying-mechanisms-in-systemic-lupus-erythematosus
#18
Lin Xie, Jinhua Xu
OBJECTIVE: T-lymphocyte apoptosis plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the underlying regulatory mechanisms of apoptosis in SLE remain unclear. The aim of this study was to explore the role of miR-98 in SLE and its underlying mechanisms. METHODS: Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to analyze miR-98 and Fas expression. Luciferase reporter assays were performed to identify miR-98 targets...
June 15, 2018: Journal of Rheumatology
https://www.readbyqxmd.com/read/29907623/unexpected-benefits-of-aging-for-favorable-responses-to-pd-1-blockade-in-melanoma
#19
Graham Pawelec
Immunosenescence might be expected to reduce the efficacy of checkpoint blockade, which depends on a functionally intact immune system. However, it seems that older melanoma patients may respond better to anti-PD1 treatment than younger patients, possibly due to their having fewer regulatory T-cells relative to CD8+ T-cells within tumour deposits.
June 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29907586/yap-is-essential-for-treg-mediated-suppression-of-anti-tumor-immunity
#20
Xuhao Ni, Jinhui Tao, Joseph Barbi, Qian Chen, Benjamin V Park, Zhiguang Li, Nailing Zhang, Andriana Lebid, Anjali Ramaswamy, Ping Wei, Ying Zheng, Xuehong Zhang, Xingmei Wu, Paolo D A Vignali, Cuiping Yang, Huabin Li, Drew Pardoll, Ling Lu, Duojia Pan, Fan Pan
Regulatory T cells (Tregs) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective anti-tumor immune responses. Foxp3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing Foxp3 expression and Treg function are not completely understood. Herein, we report that Yes-associated protein (YAP), a co-activator of the Hippo pathway, is highly expressed in Tregs and bolsters Foxp3 expression and Treg function in vitro and in vivo...
June 15, 2018: Cancer Discovery
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