Expression of CD4+CD25+Foxp3+ Regulatory T Cells, Interleukin 10 and Transforming Growth Factor β in Newly Diagnosed Type 2 Diabetic Patients

2017 ◽  
Vol 126 (02) ◽  
pp. 96-101 ◽  
Author(s):  
Ning Yuan ◽  
Hai-feng Zhang ◽  
Qi Wei ◽  
Ping Wang ◽  
Wei-ying Guo
Keyword(s):  
Insulin Resistance ◽  
T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Obese Group ◽  
Control Group ◽  
Newly Diagnosed ◽  
Significant Difference

Abstract Background Recent studies have shown that dysfunction and decrease of regulatory T cells (Tregs) correlates with insulin resistance (IR), one of the most significant mechanisms for type 2 diabetes mellitus (T2DM). To examine potential relationships among Tregs, IR, blood lipid content, and related cytokines, we investigated the frequency of CD4+CD25+Foxp3+ Tregs, as well as expression levels of interleukin 10 (IL-10) and transforming growth factor-β (TGF-β) in newly diagnosed T2DM patients. Methods Fifty-one newly diagnosed T2DM patients and 55 control individuals were enrolled. According to body mass index (BMI), the T2DM patients were grouped into non-obese and obese groups. Blood was collected in ethylene diamine tetraacetic acid (EDTA) anticoagulant tubes for detection of CD4+CD25+Foxp3+ Tregs by flow cytometry. Serum was collected to quantify IL-10 and TGF-β levels by enzyme-linked immunosorbent assay (ELISA). By comparing percentages of Tregs between non-obese and obese groups, correlation with Treg frequency, homeostasis model assessment of insulin resistance (HOMA-IR), IL-10 and TGF-β was examined. Results The percentage of CD4+CD25+Foxp3+ Tregs in the newly diagnosed T2DM group was significantly lower than in the control group (P<0.01). Further, levels of IL-10 and TGF-β were also lower in the T2DM group (P<0.05). The level of IL-10 was remarkably lower in the obese group than in the non-obese and the control groups (P<0.01), but there was no significant difference between non-obese group and the control group. The level of TGF-β was lower in obese group than in the control group (P<0.05). There was no significant difference between non-obese group and the control group. The frequency of CD4+CD25+Foxp3+ Tregs in the obese group was significantly lower than in the non-obese group (P<0.05). In the obese group, the percentage of Tregs negatively correlated with HOMA-IR and positively correlated with TGF-β (P<0.05). There was no obvious correlation between Treg and HOMA-IR in the non-obese group. Conclusion The percentage of CD4+CD25+Foxp3+ Tregs and levels of related cytokines IL-10 and TGF-β were precipitously decreased in newly diagnosed T2DM patients. Therefore, the function of Tregs in limiting the proinflammatory milieu represents an important pathogenic mediator of the development of obesity-induced IR in newly diagnosed T2DM patients. Notably, TGF-β may play an important role in this process. Thus, enhancing expression of Tregs may improve IR in newly diagnosed T2DM patients with obesity.

scholarly journals Increased circulating levels of musclin in newly diagnosed type 2 diabetic patients

2017 ◽  
Vol 14 (2) ◽  
pp. 116-121 ◽  
Author(s):  
Wen-Jia Chen ◽  
Yue Liu ◽  
Yu-Bin Sui ◽  
Bo Zhang ◽  
Xiao-Hui Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Plasma Levels ◽  
Control Group ◽  
Diabetic Patients ◽  
Model Assessment ◽  
Newly Diagnosed

Background: Musclin is a newly identified skeletal muscle–derived secretory factor, which has been recently characterized as a stimulator that induces insulin resistance in mice. However, the pathophysiological role of musclin in humans remains poorly understood. The aim of this study was to explore the potential correlations between musclin plasma levels and various metabolic parameters in patients with type 2 diabetes mellitus. Materials and methods: In this hospital-based study, plasma samples were collected from the enrolled individuals, including 38 newly diagnosed, treatment-naive type 2 diabetes mellitus patients and 41 age- and gender-matched control subjects. Plasma musclin levels were examined by radioimmunoassay. Results: Compared with the control group, musclin plasma levels were significantly higher in untreated type 2 diabetes mellitus patients. Musclin levels in the plasma of newly diagnosed type 2 diabetes mellitus patients were positively correlated with fasting plasma glucose, haemoglobin A1c, serum insulin, triglycerides and homeostasis model assessment of insulin resistance. Furthermore, multivariate logistic regression analysis showed that the level of musclin was associated with the presence of type 2 diabetes mellitus. Receiver operating characteristic curve analysis yielded an area under the curve for musclin of 0.718 in type 2 diabetes mellitus. Conclusion: The circulating concentration of musclin was significantly increased in type 2 diabetes mellitus patients. Our results suggest that musclin has a strong relationship with insulin resistance in type 2 diabetes mellitus.

scholarly journals Aberrant Expression of Long Non-Coding RNAs in Newly Diagnosed Type 2 Diabetes Indicates Potential Roles in Chronic Inflammation and Insulin Resistance

2017 ◽  
Vol 43 (6) ◽  
pp. 2367-2378 ◽  
Author(s):  
Xiaoli Wang ◽  
Xiangyun Chang ◽  
Peipei Zhang ◽  
Ling Fan ◽  
Ting Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Target Genes ◽  
Chinese Patients ◽  
Control Group ◽  
Newly Diagnosed ◽  
Aberrant Expression ◽  
Healthy Control ◽  
Non Coding Rnas

Background/Aims: Long non-coding RNAs (lncRNAs) have emerged as key players in several biological processes and complex diseases. The risk of type 2 diabetes (T2D) is determined by a combination of environmental factors and genetic susceptibility. The purpose of this study was to identify aberrant lncRNAs involved in T2D pathogenesis. Methods: Microarray analysis was performed using whole blood samples from patients newly diagnosed with T2D and healthy controls. Pathway and Gene Ontology (GO) analyses were utilized to annotate the target genes. Coding non-coding co-expression (CNC) analysis was performed to construct a co-expression network. Results: We found 55 lncRNAs and 202 mRNAs were differentially expressed in the T2D group compared to the healthy control group. Pathway and GO analyses demonstrated that dysregulated mRNAs were mainly associated with immune regulation, inflammation, and insulin resistance, whereas CNC analysis identified 10 pairs of co-expressed lncRNA-mRNAs in our patient cohort (R > 0.99). Furthermore, expression of the top three upregulated lncRNAs in the T2D group was correlated with measures of glycometabolism (P < 0.05). Conclusion: This study identified aberrantly expressed lncRNAs and mRNAs in Han Chinese patients with T2D, and demonstrated that dysregulated lncRNAs may have roles in T2D pathogenesis through regulation of inflammation and insulin resistance.

Influences of High-Dose Dexamethasone on Regulatory T Cells, Transforming Growth Factor-β1 and Interleukin-10 of Patients with Chronic ITP.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3920-3920
Author(s):  
Yun Ling ◽  
Xiangshan Cao ◽  
Ziqiang Yu ◽  
Changgeng Ruan
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Transforming Growth Factor Β1 ◽  
High Dose ◽  
Chronic Itp ◽  
High Dose Dexamethasone ◽  
Significant Difference ◽  
Tgf Β1

Abstract Immune thrombocytopenic purpura (ITP) is an autoimmune disorder and high-dose dexamethasone (HD-DXM) has been used as a first-line therapy for patients with ITP. However, little is known about the role of CD4+CD25 + regulatory T (Treg) cells, interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in the pathogenesis of chronic ITP and the effects of HD-DXM on them contained Treg cells, IL-10 and TGF-β1. In this study, we investigated the expressions of Treg cells, IL-10 and TGF-β1 in 26 untreated adult patients with chronic ITP. All patients had thrombocytopenia (platelet count &lt;50 × 109/L) for more than 6 months. We also observed short time changes of Treg cells, IL-10 and TGF-β1 after treatment with HD-DXM in these patients. The results showed that a good initial response to HD-DXM occurred in 24 of the 26 patients with chronic ITP (92.3%): the mean platelet count was (84.9±30.4)×109/L [range, (20∼150) ×109/L] one week after the initiation of treatment. The proportion of CD4+CD25+ T cells in the peripheral blood of patients with chronic ITP was significantly higher than that in normal controls(P&lt;0.001); there was no significant difference in the percentage of CD4+CD25high T cells between patients and controls ( P=0.317); but the number of CD4+ FOXP3+ T cells in patients was significantly lower than that in controls (P&lt;0.001). After 4-days treatment with HD-DXM, the numbers of CD4+ CD25+ T cells (P&lt;0.001), CD4+CD25high T cells ( P&lt;0.001), and CD4+FOXP3+ T cells ( P&lt;0.001) in patients were all significantly increased. In the serum of chronic ITP patients, the expression level of TGF-β1 was lower than that of healthy controls (P&lt;0.0001) and HD-DXM could significantly increase it; there was no significant difference in the expression level of IL-10 between patients and controls ( P&gt;0.05) and there was no remarkable change of IL-10 in patients after HD-DXM treatment (P&gt;0.05). The mRNA levels of Foxp3 and TGF-β1 gene in patients were lower than those of controls (P&lt;0.05 and P&lt;0.05); HD-DXM administration significantly increased the expressions of Foxp3 and TGF-β1 gene(P&lt;0.05 and P&lt;0.0001), which were even higher than those of controls(P&lt;0.05 and P&lt;0.05); There was a positive correlation between the Foxp3 mRNA expression and TGF-β1 after treatment with HD-DXM (r =0.403, P=0.041). These results suggest that Foxp3 and TGF-β1 gene are deficient in chronic ITP and the immunosuppressive therapy of glucocorticoids could improve the expression levels of these genes.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

scholarly journals The interleukin-10 inducing effect of transforming growth factor-β on human naive CD4+ T cells from cord blood is restricted to the TH1 subset

2006 ◽  
Vol 147 (2) ◽  
pp. 352-358
Author(s):  
B. Kapitein ◽  
M. M. Tiemessen ◽  
W. M. Liu ◽  
A. G. Van Ieperen-van Dijk ◽  
M. O. Hoekstra ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Cord Blood ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

scholarly journals Interleukin-10- and Transforming Growth Factor β-Independent Regulation of CD8+T Cells Expressing Type 1 and Type 2 Cytokines in Human Lymphatic Filariasis

2014 ◽  
Vol 21 (12) ◽  
pp. 1620-1627 ◽  
Author(s):  
Rajamanickam Anuradha ◽  
Parakkal Jovvian George ◽  
Paul Kumaran ◽  
Thomas B. Nutman ◽  
Subash Babu
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Lymphatic Filariasis ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Transforming Growth Factor Β ◽  
Necrosis Factor Alpha ◽  
Type 2 Cytokines

ABSTRACTLymphatic filariasis is known to be associated with diminished CD4+Th1 and elevated CD4+Th2 responses to parasite-specific antigens. The roles of cytokine-expressing CD8+T cells in immune responses to filarial infections are not well defined. To study the roles of CD8+T cells expressing type 1, type 2, and type 17 cytokines in filarial infections, we examined the frequencies of these cells in clinically asymptomatic, patently infected (INF) individuals, directlyex vivoand in response to parasite or nonparasite antigens; these frequencies were compared with the results for individuals with filarial lymphedema (i.e., clinical pathology [CP]) and those without active infection or pathology (i.e., endemic normal [EN]). INF individuals exhibited significant decreases in the frequencies of CD8+T cells expressing tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin-22 (IL-22) at baseline and/or in response to filarial antigens, compared with CP and EN individuals. In contrast, the same individuals exhibited significant increases in the frequencies of CD8+T cells expressing IL-4, IL-5, IL-9, IL-13, and IL-21, compared with CP and/or EN individuals. Curative treatment resulted in significantly increased frequencies of CD8+T cells expressing IL-2 and significantly decreased frequencies of CD8+T cells expressing type 2 cytokines. Finally, the regulation of these responses appears to be independent of IL-10 and transforming growth factor β (TGF-β), since blockade of IL-10 or TGF-β signaling did not significantly alter the frequencies of type 1 or type 2 cytokine-expressing CD8+T cells. Our findings suggest that alterations in the frequencies of cytokine-expressing CD8+T cells are characteristic features of lymphatic filarial infections.

Complex therapy of patients with metabolic syndrome in the early stages of its development

10.12737/7343 ◽  
2014 ◽  
Vol 8 (1) ◽  
pp. 0-0
Author(s):  
Мельник ◽  
Margarita Myelnik ◽  
Абдуллаева ◽  
A. Abdullaeva
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Glycated Hemoglobin ◽  
Control Group ◽  
Newly Diagnosed ◽  
Stages Of Development ◽  
C Peptide ◽  
Incretin Mimetics ◽  
Early Stages

This paper deals with the combination therapy of patients in the early stages of development of the metabolic syndrome (MS) according to the results of the survey and the 6-month treatment of 54 patients aged 20 to 55 years with a BMI ≥25 kg / m2 and signs of abdominal obesity. In the control group 15 of the surveyed persons with a BMI &#60; 25,0 kg/m2 at age 20 to 50 years were included . According to the classification proposed in the recommendations of the experts of GFCF for the diagnosis and treatment of MS (2009), MS source in the group of patients with a BMI ≥ 25 kg/m2 was determined in 94.2% of cases. In this study the authors used laboratory examination, including general and biochemical blood tests to determine the level of glycated hemoglobin (Hb A1c), the concentration of magnesium and malondialdehyde (MDA) in serum levels of C-peptide immuno-reactive insulin (IRI) to the calculation of indices: HOMO IR, characterizing insulin resistance (IR) and Caro, which characterizes the degree of impairment of glucose uptake. The instrumental methods were measurement of blood pressure by auscultatory method, ECG, echocardiography, ultrasound of the abdomen, CGMS-monitoring of blood glucose levels. According to the obtained data in the studied group of patients with a BMI of 25 kg/m2 statistically significant increase in blood pressure, severe insulin resistance with compensatory hyper-insulinemia, elevated levels of Hb A1c were identified. It is established that the formation of overweight in 68.5% of cases is accompanied by hypomagnesemia and activation of oxidative stress&#34;. It was confirmed by statistically significant increase in MDA content. Number of newly diagnosed diseases - hypertension, ischemic heart disease, diabetes type 2, NAFLD, patients with a BMI ≥ 25 kg/m2 was significantly higher than the con-trol, which confirms the dominant influence of overweight as a risk factor for CVD formation with impaired metabolism of glucose and lipids. To study the stages of development of MS in both groups of patients oral glu-cose tolerance test (PGT) was conducted. According to the obtained results, the patients of the studied group were divided into 3 subgroups (without carbohydrate metabolism, with IGT, with newly diagnosed type 2 diabe-tes). In the 1st subgroup concentrations of insulin and C-peptide at 30 min of the test was higher than in other subgroups and the control group, but this concentration was decreased to 120 minute test. In the 2nd subgroup of these indicators for 30 minutes were significantly lower and grew to 120 minute test. In the subgroup with newly diagnosed type 2 diabetes, this concentration of insulin and C-peptide at 30 min of the test was lower than in the control group, but the concentration was increased to 120 minute test. Monitoring blood glucose lev-els using the CGMS system helped to identify: in the 1st subgroup intermittent episodes of hyperglycemia to 5.5% daily time; significant episodes of hyperglycemia in the 3rd subgroup – 19% of the time during the day. Therefore, the first stage of correction of hyper-insulinemia and IR were: changing the receiving regime of low-calorie food and incretin mimetics appointment - exenatide. At the same time, the patients in the treatment group received drugs magnesium – Magnesium Orotate (if hypomagnesemia) and antioxidants – coenzyme Q10 and vitamin E. After 24 weeks of therapy, clinical examination demonstrated the effectiveness of treat-ment: BMI statistically significantly decreased by 8.5%, IL by 43.3%, normalization of the level of glycated hemoglobin and reduced levels of atherogenic lipids, as well as the achievement of target values of blood pressure on average for the study group were identified. Restoring the sensitivity of insulin receptors was accompanied by an increase in the level of magnesium in the blood by 47.5% and a simultaneous decrease in activity of oxidative system by 42.7%. The obtained results suggest the usefulness of the use of incretin mimetics drugs with antioxidant activity and therapy by preparations of magnesium in the prevention and treatment of MS in the early stages of development.

Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 632-642 ◽  
Author(s):  
Marco Cosentino ◽  
Anna Maria Fietta ◽  
Marco Ferrari ◽  
Emanuela Rasini ◽  
Raffaella Bombelli ◽  
...  
Keyword(s):  
T Cells ◽  
Tyrosine Hydroxylase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Down Regulation ◽  
Regulatory T Lymphocytes ◽  
Endogenous Catecholamines ◽  
Factor Α

Abstract CD4+CD25+ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-β by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-α or interferon-γ. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopaminergic receptors to a similar extent (12%-29% of the cells). Catecholamine-dependent down-regulation of Tregs is, however, selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of Treg function.

Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1162-1169 ◽  
Author(s):  
Megan K. Levings ◽  
Silvia Gregori ◽  
Eleonora Tresoldi ◽  
Sabrina Cazzaniga ◽  
Chiara Bonini ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Cellular Therapy ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Peripheral Tolerance ◽  
Immature Dendritic Cells ◽  
Tr1 Cells

Abstract Dendritic cells (DCs) are specialized antigen-presenting cells that monitor the antigenic environment and activate naive T cells. The role of DCs is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. Indeed, if a naive T cell encounters its antigen on immature DCs (iDCs), it may differentiate into a T-regulatory (Tr) rather than a T-effector cell. However, little is known about the mechanisms by which iDCs differentiate Tr cells. We developed a standardized and highly reproducible protocol to differentiate Tr cells by repetitive exposure of naive peripheral blood CD4+ T cells to allogeneic iDCs. The resultant Tr cells are phenotypically and functionally identical to type 1 Tr (Tr1) cells because their generation requires production of IL-10 by iDCs, and they suppress T-cell responses through an interleukin-10 (IL-10)– and a transforming growth factor β (TGF-β)–dependent mechanism. In addition, Tr1 cells induced by iDCs do not require the presence of CD4+CD25+ Tr cells for their generation, nor do they express high constitutive levels of CD25 or the transcription factor FoxP3. Thus, iDCs can drive the differentiation of Tr1 cells and can be used to generate large numbers of alloantigen-specific Tr1 cells for clinical use as a cellular therapy to restore peripheral tolerance.

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