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https://www.readbyqxmd.com/read/27903296/factors-affecting-long-term-efficacy-of-t-regulatory-cell-based-therapy-in-type-1-diabetes
#1
Natalia Marek-Trzonkowska, Małgorzata Myśliwiec, Dorota Iwaszkiewicz-Grześ, Mateusz Gliwiński, Ilona Derkowska, Magdalena Żalińska, Maciej Zieliński, Marcelina Grabowska, Hanna Zielińska, Karolina Piekarska, Anna Jaźwińska-Curyłło, Radosław Owczuk, Agnieszka Szadkowska, Krystyna Wyka, Piotr Witkowski, Wojciech Młynarski, Przemysława Jarosz-Chobot, Artur Bossowski, Janusz Siebert, Piotr Trzonkowski
BACKGROUND: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment. METHODS: The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 10(6)/kg b.w. of autologous expanded CD3(+)CD4(+)CD25(high)CD127(-) Tregs...
December 1, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27891128/immune-imbalances-in-non-alcoholic-fatty-liver-disease-from-general-biomarkers-and-neutrophils-to-interleukin-17-axis-activation-and-new-therapeutic-targets
#2
REVIEW
Feliciano Chanana Paquissi
Non-alcoholic fatty liver disease (NAFLD) is an increasing problem worldwide and is associated with negative outcomes such as cirrhosis, hepatocellular carcinoma, insulin resistance, diabetes, and cardiovascular events. Current evidence shows that the immune response has an important participation driving the initiation, maintenance, and progression of the disease. So, various immune imbalances, from cellular to cytokines levels, have been studied, either for better compression of the disease pathophysiology or as biomarkers for severity assessment and outcome prediction...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27880731/smad4-in-t-cells-plays-a-protective-role-in-the-development-of-autoimmune-sj%C3%A3-gren-s-syndrome-in-the-nonobese-diabetic-mouse
#3
Donghee Kim, Jae Young Kim, Hee-Sook Jun
We investigated the role of Smad4, a signaling molecule of the TGF-beta pathway, in T cells on the pathology of Sjögren's syndrome (SS) in nonobese diabetic (NOD) mice, an animal model of SS. T cell-specific Smad4-deleted (Smad4fl/fl,CD4-Cre; Smad4 tKO) NOD mice had accelerated development of SS compared with wild-type (Smad4+/+,CD4-Cre; WT) NOD mice, including increased lymphocyte infiltration into exocrine glands, decreased tear and saliva production, and increased levels of autoantibodies at 12 weeks of age...
November 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27872621/combining-theoretical-and-experimental-techniques-to-study-murine-heart-transplant-rejection
#4
Julia C Arciero, Andrew Maturo, Anirudh Arun, Byoung Chol Oh, Gerald Brandacher, Giorgio Raimondi
The quality of life of organ transplant recipients is compromised by complications associated with life-long immunosuppression, such as hypertension, diabetes, opportunistic infections, and cancer. Moreover, the absence of established tolerance to the transplanted tissues causes limited long-term graft survival rates. Thus, there is a great medical need to understand the complex immune system interactions that lead to transplant rejection so that novel and effective strategies of intervention that redirect the system toward transplant acceptance (while preserving overall immune competence) can be identified...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27872297/singular-role-for-t-bet-cxcr3-regulatory-t-cells-in-protection-from-autoimmune-diabetes
#5
Tze Guan Tan, Diane Mathis, Christophe Benoist
Foxp3(+) regulatory T (Treg) cells are crucial for restraining inflammation in a variety of autoimmune diseases, including type 1 diabetes (T1D). However, the transcriptional and functional phenotypes of Treg cells within the pancreatic lesion remain poorly understood. Here we characterized pancreas-infiltrating Treg cells in the NOD mouse model of T1D and uncovered a substantial enrichment of the Treg subpopulation expressing the chemokine receptor CXCR3. Accumulation of CXCR3(+) Treg cells within pancreatic islets was dependent on the transcription factor T-BET, and genetic ablation of T-BET increased the onset and penetrance of disease, abrogating the sex bias normally seen in the NOD model...
November 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27815439/are-regulatory-t-cells-defective-in-type-1-diabetes-and-can-we-fix-them
#6
REVIEW
Anabelle Visperas, Dario A A Vignali
Regulatory T cells (Tregs) are critical regulators of peripheral immune tolerance. Treg insufficiency can lead to autoimmune disorders, including type 1 diabetes (T1D). Increasing evidence in mouse models of T1D, as well as other autoimmune disorders, suggests that there are defects in Treg-mediated suppression. Indeed, whereas Treg frequency in the peripheral blood of T1D patients is unaltered, their suppressive abilities are diminished compared with Tregs in healthy controls. Although expression of the transcription factor Foxp3 is a prerequisite for Treg development and function, there are many additional factors that can alter their stability, survival, and function...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27799873/development-of-auto-antigen-specific-regulatory-t-cells-for-diabetes-immunotherapy
#7
REVIEW
Jianxun Song
CD4(+) regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs...
October 2016: Immune Network
https://www.readbyqxmd.com/read/27797910/islet-expressed-cxcl10-promotes-autoimmune-destruction-of-islet-iso-grafts-in-mice-with-type-1-diabetes
#8
Christine Bender, Selina Christen, Klaus Scholich, Monika Bayer, Josef M Pfeilschifter, Edith Hintermann, Urs Christen
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells in the pancreas. Thereby the chemokine CXC-motif ligand 10 (CXCL10) plays an important role in the recruitment of autoaggressive lymphocytes to the islets of Langerhans. Transplantation of isolated islets as a promising therapy of T1D has been hampered by early graft rejection. Here, we investigated the influence of CXCL10 on the autoimmune destruction of islet iso-grafts using RIP-LCMV mice expressing a lymphocytic choriomeningitis virus (LCMV) protein in the β-cells...
October 26, 2016: Diabetes
https://www.readbyqxmd.com/read/27796442/congenic-mapping-identifies-a-novel-idd9-subregion-regulating-type-1-diabetes-in-nod-mice
#9
Bixuan Lin, Ashley E Ciecko, Erin MacKinney, David V Serreze, Yi-Guang Chen
Type 1 diabetes (T1D) results from complex interactions between genetic and environmental factors. The nonobese diabetic (NOD) mouse develops spontaneous T1D and has been used extensively to study the genetic control of this disease. T1D is suppressed in NOD mice congenic for the C57BL/10 (B10)-derived Idd9 resistance region on chromosome 4. Previous studies conducted by other investigators have identified four subregions (Idd9.1, Idd9.2, Idd9.3, and Idd9.4) where B10-derived genes suppress T1D development in NOD mice...
October 28, 2016: Immunogenetics
https://www.readbyqxmd.com/read/27777959/changes-of-regulatory-t-cells-and-of-proinflammatory-and-immunosuppressive-cytokines-in-patients-with-type-2-diabetes-mellitus-a-systematic-review-and-meta-analysis
#10
Yong-Chao Qiao, Jian Shen, Lan He, Xue-Zhi Hong, Fang Tian, Yan-Hong Pan, Ling Liang, Xiao-Xi Zhang, Hai-Lu Zhao
Objective. The aim of this study was to investigate the changes of regulatory T cells (Treg), interleukin-6 (IL-6), IL-10, transforming growth factor-β (TGF-β), and tumor necrosis factor-alpha (TNF-α) in patients with type 2 diabetes mellitus (T2DM). Methods. We performed a comprehensive search up to July 2016 for all clinical studies about the changes of Treg, IL-6, IL-10, IL-17, TGF-β, and TNF-α in T2DM patients versus healthy controls. Results. A total of 91 articles (5642 cases and 7378 controls) were included for this meta-analysis...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27764529/t-lymphocyte-and-glycemic-status-after-vitamin-d-treatment-in-type-1-diabetes-a-randomized-controlled-trial-with-sequential-cross-over
#11
D Bogdanou, M Penna-Martinez, N Filmann, T L Chung, Y Moran-Auth, J Wehrle, C Cappel, S Huenecke, E Herrmann, U Koehl, K Badenhoop
BACKGROUND: Type 1 diabetes mellitus (T1D) is mediated by autoaggressive T effector cells with an underlying regulatory T cell (Treg) defect. Vitamin D (VD) deficiency is highly prevalent in T1D which can aggravate immune dysfunction. High dose VD treatment may enhance Tregs and improve metabolism in T1D patients. METHODS: In a randomized, double-blind, placebo-controlled trial with cross-over design, patients received either for three months cholecalciferol 4000 IU/d, followed by three months placebo or the sequential alternative...
October 20, 2016: Diabetes/metabolism Research and Reviews
https://www.readbyqxmd.com/read/27761063/il-33-effect-on-quantitative-changes-of-cd4-cd25-high-foxp3-regulatory-t-cells-in-children-with-type-1-diabetes
#12
Monika Ryba-Stanisławowska, Paulina Werner, Maria Skrzypkowska, Agnieszka Brandt, Jolanta Myśliwska
IL-33 is an IL-1 cytokine family member, with ability to induce both Th1 and Th2 immune responses. It binds to ST2 receptor, whose deficiency is associated with enhanced inflammatory response. The most recent studies have shown the immunoregulatory effect of IL-33 on Tregs in animal models. As type 1 diabetes is an autoimmune, inflammatory disease, where Treg defects have been described, we aimed to analyze the in vitro influence of recombinant IL-33 on quantitative properties of regulatory CD4(+)CD25(high)FOXP3(+) T cells...
2016: Mediators of Inflammation
https://www.readbyqxmd.com/read/27755503/c-c-chemokine-receptor-type-2-ccr2-dependent-migration-of-myeloid-derived-suppressor-cells-in-protection-of-islet-transplants
#13
Jie Qin, Yusuke Arakawa, Miwa Morita, John J Fung, Shiguang Qian, Lina Lu
BACKGROUND: Islet transplantation is a promising therapeutic approach for restore the physical response to blood glucose in type 1 diabetes. Current chronic use of immunosuppressive reagents for preventing islet allograft rejection is associated with severe complications. In addition, many of the immunosuppressive drugs are diabetogenic. The induction of transplant tolerance to eliminate the dependency on immunosuppression is ideal, but remains challenging. METHODS: Addition of hepatic stellate cells allowed generation of myeloid-derived suppressor cells (MDSC) from precursors in mouse bone marrow...
October 17, 2016: Transplantation
https://www.readbyqxmd.com/read/27753990/ed-05-2-interaction-of-gut-dysbiosis-and-innate-immune-dysfunction-in-the-development-of-metabolic-syndrome
#14
Myung-Shik Lee
Low-grade systemic inflammation in adipose tissues or liver, is an important etiologic factor in insulin resistance. LPS is an important element causing such metabolic inflammation, and intestinal flora is considered a major source of systemic LPS. We studied changes of intestinal microbiota associated with high-fat diet (HFD) that causes insulin resistance and metabolic stress. 16S rRNA gene sequencing showed that HFD significantly decreased the abundance of a mucin-degrading bacterium Akkermansia muciniphila compared to control diet...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27753836/sy-05-2-progression-of-hypertensive-heart-disease-new-therapeutic-approach
#15
Masatsugu Horiuchi
Hypertensive patients have greater chances of such cardiovascular events as stroke, coronary heart disease, heart or renal failure, peripheral artery disease, and dementia. It is also well recognized that diabetes increases the cardiovascular risks in concert with hypertension. Therefore, main goals for an innovation of anti-hypertensive therapy would be to achieve further risk reduction by targeting the functional, metabolic, and structural alterations associated with hypertension. Professors Dzau and Braunwald et al proposed the concept of "the cardiovascular disease continuum" in 1991, and that hypertension may trigger the chain of events, leading to end-stage heart disease; however, this concept was quite new at that time, and there was some discussion whether "the cardiovascular disease continuum" is true or not...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27745778/mucosal-administration-of-cd3-specific-monoclonal-antibody-inhibits-diabetes-in-nod-mice-and-in-a-preclinical-mouse-model-transgenic-for-the-cd3-epsilon-chain
#16
Chantal Kuhn, Rafael M Rezende, Andre Pires da Cunha, Fabrice Valette, Francisco J Quintana, Lucienne Chatenoud, Howard L Weiner
CD3-specific monoclonal antibody (mAb) treats autoimmune disease in animal models and has shown promise in clinical trials of type 1 diabetes. Whereas intravenous administration of CD3-specific mAb acts primarily by transient depletion of activated effector T cells, oral CD3-specific mAb acts primarily by the induction Tregs. We investigated whether oral CD3-specific mAb inhibits disease in non obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, closely resembling human type 1 diabetes...
October 10, 2016: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27727279/regulatory-t-cell-responses-in-participants-with-type-1-diabetes-after-a-single-dose-of-interleukin-2-a-non-randomised-open-label-adaptive-dose-finding-trial
#17
John A Todd, Marina Evangelou, Antony J Cutler, Marcin L Pekalski, Neil M Walker, Helen E Stevens, Linsey Porter, Deborah J Smyth, Daniel B Rainbow, Ricardo C Ferreira, Laura Esposito, Kara M D Hunter, Kevin Loudon, Kathryn Irons, Jennie H Yang, Charles J M Bell, Helen Schuilenburg, James Heywood, Ben Challis, Sankalpa Neupane, Pamela Clarke, Gillian Coleman, Sarah Dawson, Donna Goymer, Katerina Anselmiova, Jane Kennet, Judy Brown, Sarah L Caddy, Jia Lu, Jane Greatorex, Ian Goodfellow, Chris Wallace, Tim I Tree, Mark Evans, Adrian P Mander, Simon Bond, Linda S Wicker, Frank Waldron-Lynch
BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs...
October 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27686408/impact-of-t-cell-specific-smad4-deficiency-on-the-development-of-autoimmune-diabetes-in-nod-mice
#18
Donghee Kim, Song Mi Lee, Hee-Sook Jun
Type 1 diabetes results from autoimmune-mediated pancreatic beta cell destruction and TGF-β is known to play a preventive role in type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we investigated the role of Smad4, a key molecule for Smad-dependent TGF-β signaling, in T cells of NOD mice in the pathogenesis of autoimmune diabetes. We generated T cell-specific Smad4 knockout (Smad4 tKO) NOD mice and assessed the pathological and immunological changes. Smad4 tKO showed earlier onset and increased incidence of diabetes than wild-type (WT) NOD mice...
September 30, 2016: Immunology and Cell Biology
https://www.readbyqxmd.com/read/27683634/tregs-and-kidney-from-diabetic-nephropathy-to-renal-transplantation
#19
REVIEW
Periklis Dousdampanis, Kostantina Trigka, Athanasia Mouzaki
Kidney transplantation is recognised as the most effective treatment for patients with end-stage renal disease (ESRD). Kidney transplantation continues to face several challenges including long-term graft and patient survival, and the side effects of immunosuppressive therapy. The tendency in kidney transplantation is to avoid the side effects of immunosuppresants and induce immune tolerance. Regulatory T-cells (Tregs) contribute to self-tolerance, tolerance to alloantigen and transplant tolerance, mainly by suppressing the activation and function of reactive effector T-cells...
September 24, 2016: World Journal of Transplantation
https://www.readbyqxmd.com/read/27669730/anti-thymocyte-globulin-g-csf-combination-therapy-leads-to-sustained-immunomodulatory-and-metabolic-effects-in-a-subset-of-responders-with-established-type-1-diabetes
#20
Michael J Haller, Stephen E Gitelman, Peter A Gottlieb, Aaron W Michels, Daniel J Perry, Andrew R Schultz, Maigan A Hulme, Jonathan J Shuster, Baiming Zou, Clive H Wasserfall, Amanda Posgai, Clayton E Mathews, Todd M Brusko, Mark A Atkinson, Desmond A Schatz
Low-dose anti-thymocyte globulin (ATG) + pegylated granulocyte-colony stimulating factor (G-CSF) preserves beta cell function for at least 12-months in type 1 diabetes (T1D). Herein, we describe metabolic and immunologic parameters 24-months following treatment. Patients with established T1D (duration 4-24 months) were randomized to ATG and peg-G-CSF (N=17) or placebo (N=8). Primary outcomes included AUC C-peptide following mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "Super-responders" (24-month C-peptide ≥ baseline), and "Non-responders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome...
September 26, 2016: Diabetes
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