Treg Cells In Patients Research Articles

Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial

An improper balance of regulatory/effector T (Treg/Teff) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) induced Treg cell expansion and activation and clinical improvement in patients with hepatitis-C-virus-induced vasculitis. We aimed to establish which low doses of IL2 would be safe and induce Treg cells in patients with type 1 diabetes, considering that: (1) type 1 diabetes might be linked to alteration of the IL2/IL2R activation pathway; (2) activation of pathogenic Teff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes. This was a single-centre phase 1/2 study. 24 adult patients (18-55 years) with established insulin-dependent type 1 diabetes and at least one diabetes-related autoantibody were enrolled and randomly assigned (in a 1:1:1:1 ratio, by computer-generated randomisation list, with block size four) to placebo or IL2 at 0.33 MIU/day, 1 MIU/day, or 3 MIU/day for a 5-day course and were followed up for 60 days. All investigators and participants were masked to assignment. The primary outcome was change in Treg cells, measured by flow cytometry, and expressed as a percentage of CD4+ T cells, from day 1 to day 60. This trial is registered with ClinicalTrials.gov, number NCT01353833. Six patients were assigned to each group between June 1, 2011, and Feb 3, 2012. IL2 was well tolerated at all doses, with no serious adverse events. However, there was a dose-response association for non-serious adverse events during the treatment phase (days 1-6); one patient in the placebo group, three patients in the 0.33 MIU group, five patients in the 1 MIU group, and six patients in the 3 MIU group had non-serious adverse events. The most common adverse events in the treatment phase were injection-site reaction (no patients with placebo vs three patients with 0.33 MIU and 1 MIU vs two patients with 3 MIU) and influenza-like syndrome (no patients with placebo vs one patient with 0.33 MIU and 1 MIU vs four patients with 3 MIU). After the treatment phase, adverse events did not differ between groups. IL2 did not induce deleterious changes in glucose-metabolism variables. IL2 induced a dose-dependent increase in the proportion of Treg cells, significant at all doses compared with placebo (placebo mean increase 0.5% [SD 0.4]; 0.33 MIU 2.8% [1.2], p=0.0039; 1 MIU 3.9% [1.8], p=0.0039; 3 MIU 4.8% [1.9] p=0.0039). We have defined a well-tolerated and immunologically effective dose range of IL2 for application to type 1 diabetes therapy and prevention, which could be relevant to other disorders in which a Treg cell increase would be desirable.

The changes of circulating Tc17 and Treg cells in the patients with colorectal adenoma and the pa-tients with colorectal cancer

Objective To observe the changes of circulating Tc 17 and Treg cells in the patients with colorectal adenoma（CRA）and the patients with colorectal cancer （CRC）and to investigate the correla-tions between them.Methods Peripheral bloods were collected from 63 patients （30 CRA and 33 CRC） and 20 healthy subjects .The proportions of circulating Tc 17 and Treg cells in peripheral blood mononuclear cells （ PBMCs） were detected by flow cytometry .The serum levels of IL-17A and IL-23 were measured by ELISA.Results Compared with healthy controls , the proportions of circulating Tc 17 and Treg cells as well as the serum levels of IL-17 A and IL-23 in CRA and CRC groups were significantly up-regulated （ P〈0.05）.The proportions of circulating Tc17 cells and the serum levels of IL-17A and IL-23 in CRC group were significantly higher than those in CRA group （P〈0.05）, but there was no significant difference in the expressions of Treg cells between the two groups .As the disease progressed , the proportions of circulating Tc17 cells and the serum levels of IL-17A and IL-23 in CRAⅠgroup and the early CRC group were respec-tively higher than those in CRAⅡgroup and the advanced CRC group （P〈0.05）, while the expressions of Treg cells was just the opposite , and no correlation between the expressions of Tc 17 and Treg cells was found （r=-0.227, P=0.073）.Conclusion The changes in the percentage of Tc17 cells in peripheral blood are contrary to Treg cells in patients with CRA or CRC as the disease progresses , but there is no correlation be-tween them . Key words: Colorectal adenoma; Colorectal cancer; Tc17 cell; Treg cell; Cytokine

The effects of sIL-2R in plasma on regulatory T cells in children with acute Kawasaki disease

Objective To investigate the effects of sIL-2R in plasma on regulatory T cells （Treg） in children with Kawasaki disease （ KD ） .Methods Thirty-three children with KD and fourteen age-matched healthy children were enrolled in this study .The proportions of CD4＋CD25＋Foxp3＋Treg cells in pe-ripheral blood and mean fluorescence intensity （MFI） of phosphorylated-STAT5 （pSTAT5） protein in CD4＋CD25＋T cells were analyzed by flow cytometry .The concentrations of sIL-2R, IL-2, IL-7 and IL-15 in plas-ma were measured by cytometric bead array （ CBA ） .Real-time PCR was performed to detect the gene ex-pressions of Foxp3, GITR, CTLA4, IL-2Rα, IL-2Rβand IL-2Rγat mRNA level as well as the expressions of IL-17A and ROR-γt at mRNA level in CD4＋CD25-T cells.Results （1） Compared with the control group, the proportions of CD4＋CD25＋Foxp3＋Treg cells in peripheral blood from patients with KD and the expressions of associated factors including Foxp 3, GITR and CTLA-4 at mRNA level were significantly down-regulated （P0.05）.（4）The expressions of IL-2Rαand IL-2Rβat mRNA level in CD4＋CD25＋T cells from patients with acute KD were lower than those of the healthy subjects （P0.05）.The concentrations of sIL-2R in plasma were negatively correlated with the expressions of IL-2Rβand Foxp3 at mRNA level and pSTAT5 at protein level （P〈0.05）.The expression of pSTAT5 protein had positive correlation with the ex-pression of Foxp3 at mRNA level （P〈0.05）.Conclusion Aberrant IL-2/STAT5 signaling pathway media-ted by significantly increased concentration of sIL-2R in plasma might be one of the factors leading to down-regulation of Treg cells in patients with acute KD . Key words: sIL-2R; IL-2; pSTAT5; Kawasaki disease; Regulatory T cells

Imbalanced Frequencies of Th17 and Treg Cells in Acute Coronary Syndromes Are Mediated by IL-6-STAT3 Signaling

AimsExtensive evidence suggests inflammatory components participate in the pathogenic processes of acute coronary syndromes (ACS). In this study, we aimed to elucidate the role and mechanism underlying the imbalance of Th17 and Treg cell peripheral populations in the pathogenesis of ACS.Methods and ResultsUsing a flow cytometric analysis, we observed a significantly increased frequency of Th17 cells and a concurrently decreased CD4+CD25+Foxp3+ Treg cells in patients with ACS. To elucidate the mechanism of Th17/Treg imbalance in ACS, 22 inflammatory cytokines were measured using multiplexed immunobead-based assays. Of six elevated cytokines in ACS patients, only IL-6 was positively correlated with a higher Th17 cell level (r = 0.39, P<0.01). Relying on IL-6 stimulating and neutralizing studies, we demonstrated a direct role for IL-6 in sera from ACS patients with an increased frequency of Th17 cells. IL-6 induces the differentiation of Th17 cells from naïve CD4+ T cells through STAT3 activation and RORγt induction. However, we observed that high levels of TGF-β1 inhibited IL-6-dependent Th17 cell differentiation, indicating a complex interplay between the two cytokines in the control of Th17 and Treg cell populations.ConclusionsOur results demonstrate the role of IL-6-STAT3 signaling in ACS through increased Th17 cell differentiation. These findings indicate that IL-6 neutralizing strategies could present novel therapeutic avenues in the treatment of ACS.

Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders

A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4+CD25brightFoxP3+; nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.

Expression of blood Th17 and CD4(+) CD25(+) Treg cells in patients with aplastic anemia

This study was aimed to investigate the expression of blood Th17 and CD4(+) CD25(+) regulatory T cells (Treg) in the patients with aplastic anemia (AA). Forty-five patients with AA were enrolled into this study, and were divided into mild aplastic anemia (MAA) group (n = 25) and severe aplastic anemia group (SAA) (n = 20), blood cell count was recorded. 15 healthy donors were enrolled as control. Proportions of blood Th17 and CD4(+) CD25(+) Treg cells were determined by flow cytometry. The serum levels of IL-17, IFN-γ and TNF-α, as well as their concentrations in culture supernatant of phytohemagglutinin (PHA) -stimulated peripheral blood mononuclear cells, were measured by ELISA. The results showed that the proportions of blood Th17 cells and concentration of blood serum IL-17 and IFN-γ increased in patients with SAA, compared with MAA and normal controls, but CD4(+) CD25(+) Foxp3(+) Treg cells obviously decreased in patients with SAA. The concentrations of IL-17 and IFN-γ significantly increased in culture supernatant of SAA group. Hemoglobin level in the patients with AA negatively correlated with the population of Th17 cells and serum IL-17 level, whereas positively correlated with the expression of CD4(+) CD25(+)Treg cells. It is concluded that the increased response of Th17 cells and deficiency of CD4(+) CD25(+) Treg cells present in severe aplastic anemia. The severity of anemia may be related with the imbalance between Th17 and CD4(+) CD25(+)Treg cell response.

Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3

In patients with persistent upper airway inflammation, the number of forkhead box protein 3 (Foxp3)(+) regulatory T (Treg) cells is reduced, but the regulation of Foxp3 expression in Treg cells is poorly understood. We investigated the interaction between suppressor of cytokine signaling 3 (SOCS3) and Foxp3 expression in the airway mucosa. Expression of SOCS3 and Foxp3 was measured in tissue from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and control tissue. Coexpression of SOCS3 and Foxp3 was evaluated in PBMCs and in tissue from patients with CRSwNP. We also switched off and overexpressed SOCS3 in tissue from patients with CRSwNP and in pancreatic carcinoma epithelial-like cell line (PANC-1) cells and examined the effect on Foxp3 expression. SOCS3 gene and protein expression was upregulated in inflammatory cells in airway mucosa, whereas Foxp3 gene and protein expression was downregulated. Mucosal Treg cells coexpressed both proteins. Switching off the expression of SOCS3 in human airway mucosa resulted in Foxp3 upregulation, whereas inducing it in PANC-1 cells led to Foxp3 downregulation. We also found that phosphorylation of signal transducer and activator of transcription (STAT) 3 was decreased in inflamed mucosa, and we hypothesized that SOCS3 was responsible. Phosphorylation of STAT3 increased on silencing SOCS3 expression in inflamed mucosa and decreased on SOCS3 plasmid transfection in PANC-1 cells. For the first time, we demonstrate that SOCS3 and Foxp3 are coexpressed in Treg cells in human nasal mucosa and that SOCS3 negatively regulates Foxp3 expression in human airway mucosa, possibly through phosphorylation of STAT3. Hence SOCS3 could be a potential target for restoring Foxp3 expression in Treg cells in patients with persistent mucosal inflammation.

An increased ratio of Th2/Treg cells in patients with moderate to severe asthma

Background Recent studies have shown that T helper type-2 (Th2) cells can induce the apoptosis of CD4+CD25+ Treg cells or resist the immunosuppressive effect of Treg cells. We hypothesize that an imbalance of Th2/Treg is present in patients with allergic asthma. Methods Twenty-two patients with mild asthma, 17 patients with moderate to severe asthma, and 20 healthy donors were enrolled. All patients were allergic to house dust mites. The proportion of peripheral blood CD4+CD25+ Treg cells and Th2 cells were determined by flow cytometry. The concentration of interleukin (IL)-10, transforming growth factor (TGF)-β and IL-4 in plasma was determined by enzyme linked immunosorbent assay. In these subjects, peripheral blood mononuclear cells from 17 mild asthmatic patients, 13 moderate to severe asthmatic patients and 14 healthy donors were acquired and expression of forkhead box P3 (Foxp3) and GATA-3 mRNA was detected by reverse-transcriptase polymerase chain reaction. Results Compared with healthy donors and patients with mild asthma, the percent of CD4+CD25+ Treg cells and plasma IL-10 levels were decreased in patients with moderate to severe asthma. There were no significant differences in Foxp3 mRNA expression among three groups, but a downward trend seen among patients with asthma. However, the percent of Th2 cells, IL-4 levels and expression of GATA-3 mRNA was markedly higher in patients with mild and moderate to severe asthma than in the control group. The ratio of Th2/Treg and their cytokines was increased in allergic asthma, especially for moderate to severe asthma. The ratio of GATA-3/Foxp3 mRNA was also increased in allergic asthma. In patients with moderate to severe asthma, the percentage of peripheral blood Treg cells was negatively correlated to the percentage of Th2 cells and IL-4 levels. Conclusions The decline of CD4+CD25+ Treg cells in patients with moderate to severe asthma may play an important role in progress of the disease. Furthermore, the deficiency of CD4+CD25+ Treg cells was associated with the over-expression of Th2 response.

FRI0266 The mechanism of umbilical cord mesenchymal stem cells in the upregulation of regulatory t cells by tgf-b1 in systemic lupus erythematosus

ObjectivesThe aim of this study is to investigate the mechanism of umbilical cord mesenchymal stem cells (UC-MSC) in the upregulation of peripheral regulatory T cells in patients with systemic lupus...

AB0223 Effects of glucocorticoids on the expression of glucocorticoid-induced tumor necrocisis factor receptor and apotosis of the regulatory T cells in patients with systemic lupus erythematosus

BackgroundRegulatory T cells (Treg cells)contribute to the process of immune suppression. Many studies reported that Treg cells were unbalanced in patients with systemic lupus erythematosus (SLE). The glucocorticoid-induced tumor necrosis...

Dysregulation of CD4+CD25high T Cells in the Synovial Fluid of Patients With Antibiotic‐Refractory Lyme Arthritis

To examine the role of immune dysregulation in antibiotic-refractory Lyme arthritis by comparing the phenotype, frequency, and function of CD4+ Teff cells and Treg cells in patients with antibiotic- responsive arthritis and patients with antibiotic-refractory arthritis. Matched peripheral blood and synovial fluid samples from 15 patients with antibiotic-responsive arthritis were compared with those from 16 patients with antibiotic-refractory arthritis, using flow cytometry, suppression assays, and cytokine assays. Critical differences between the 2 patient groups were observed in the synovial fluid CD4+CD25(high) population, a cell subset usually composed of FoxP3-positive Treg cells. In patients with antibiotic-refractory arthritis, this cell population often had fewer FoxP3-positive cells and a greater frequency of FoxP3-negative (Teff) cells compared with patients with antibiotic-responsive arthritis. Moreover, the expression of glucocorticoid-induced tumor necrosis factor receptor and OX40 on CD4+CD25(high) cells was significantly higher in the antibody-refractory group. Suppression assays showed that CD4+CD25(high) cells in patients with antibiotic-refractory arthritis did not effectively suppress proliferation of CD4+CD25- cells or secretion of interferon-γ and tumor necrosis factor α, whereas those cells in patients with antibiotic-responsive arthritis did suppress proliferation of CD4+CD25- cells and secretion of interferon-γ and tumor necrosis factor α. Finally, in the antibiotic-refractory group, higher ratios of CD25(high) FoxP3-negative cells to CD25(high) FoxP3-positive cells correlated directly with a longer duration of arthritis after antibiotic treatment. Patients with antibiotic-refractory Lyme arthritis often have lower frequencies of Treg cells, higher expression of activation coreceptors, and less effective inhibition of proinflammatory cytokines. This suggests that immune responses in these patients are excessively amplified, leading to immune dysregulation and antibiotic-refractory arthritis.

725 The Balance Between T Helper 17 and FOXP3+ T Regulatory Cells in Patients With Chronic Hepatitis C: Relation to Disease Activity and Hepatic Fibrosis

Introduction T helper (Th)17 cells, a newly identified subset of Th cells, are major mediators of inflammation-associated disease and have a reciprocal developmental relationship with the immunosuppressive T regulatory (Treg) cells, which actively restrain the inflammatory response. The present work was designed to study the balance between Th17 cells and Treg cells in patients with chronic hepatitis C (CHC) in relation to disease activity and severity of hepatic fibrosis. Methods Twenty patients with treatment-naive CHC and 20 healthy subjects were included in the study. The Th cells, Th17 cells and Treg cell subsets in fresh whole blood samples were identified as CD3 + CD4 + , CD4 + IL17A + and CD4 + CD25 + FoxP3 + cells respectively using flow cytometry and expressed as percentages of total lymphocytic count. Serum IL17 levels were measured using solid phase sandwich enzyme linked immunosorbant assay kit. Liver biopsies from patients with CHC were examined to assess histological activity grade and fibrosis stage according to METAVIR scoring system. Liver-infiltrating CD4 + (Th cells), IL17A + cells (Th17 cells) and FoxP3 + cells (Treg cells) were detected by immunohistochemical staining and their proportions were determined as ratios of infiltrating CD4 + Th cells. Results Patients with CHC showed significant increases in the percentage of Th17 cells, Th17 cells/FoxP3 + Treg cells ratio in peripheral blood and serum IL17 levels and a significant decrease in the percentage of circulating FoxP3 + Treg cells compared with healthy subjects (p + Th cells were not statistically different between the two groups (p=0.284). The proportions of liver-infiltrating IL17A + cells and FoxP3 + cells of the total intrahepatic CD4 + cell population were inversely correlated and showed positive correlations with the percentages of circulating Th17 cells and FoxP3 + Treg cells respectively in patients with CHC (p + cells and IL17A + cells/FoxP3 + cells ratio and serum IL17 levels and were inversely correlated with the proportion of liver-infiltrating FoxP3 + cells (p Conclusion In patients with CHC, the CD4 + Th cell phenotype is skewed towards the IL17 producing-Th phenotype. The imbalance between Th17 and Foxp3 + Treg cells plays an important role in disease progression and hepatic fibrosis in CHC. Competing interests None declared.

Mechanism of umbilical cord mesenchymal stem cells in the up-regulation of regulatory T cells by transforming growth factor β1 in systemic lupus erythematosus

To explore the mechanism of umbilical cord mesenchymal stem cells (UC-MSC) in the up-regulation of peripheral regulatory T cells in patients with systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells (PBMC) from 20 SLE patients and normal controls were co-cultured with UC-MSC at different ratios respectively for 72 hours. And the proportions of CD4+CD25+Foxp3+regulatory T cells were analyzed by flow cytometry. PBMC and sera from active SLE patients and normal controls were used to stimulate UC-MSC. The expressions of transforming growth factor β1 (TGF-β1) on UC-MSC were detected by real-time fluorescence quantitative polymerase chain reaction (real-time PCR). The supernatant level of TGF-β1 was determined by enzyme-linked immunosorbent assay (ELISA). And the TGF-β1 small interfering RNA (siRNA) was used to interfere with the TGF-β1 expression on UC-MSC and determine its effect on the regulation of SLE Treg cells. TGF-β1 inhibitor was added into the culture system of UC-MSC and PBMC from active SLE patients to observe its role on the up-regulation of Treg cells by UC-MSC. UC-MSC could dose-dependently up-regulate the peripheral CD4+CD25+Foxp3+Treg proportion in SLE patients. And such an effect was not dependent on cell-cell contact. UC-MSC had no regulatory effect on Treg cells in normal controls. Compared with the non-stimulated and normal PBMC stimulated groups, PBMC from SLE patients significantly promoted TGF-β1 mRNA expression on UC-MSC (relative gene expression was 1.00 ± 0.09, 1.95 ± 0.62, 4.20 ± 2.34 respectively, both P < 0.05). The supernatant level of TGF-β1 was significantly elevated in the presence of SLE PBMC. Sera of SLE patients (5%) enhanced TGF-β1 mRNA expression on UC-MSC and it was significantly higher than fetal bovine serum cultured group (12.19 ± 4.49 vs 1.33 ± 0.06, P < 0.01) and normal individual sera cultured group (2.53 ± 0.72, P < 0.01). Additionally, TGF-β1 siRNA interfered UC-MSC failed to up-regulate Treg cells in SLE patients . Furthermore, TGF-β1 specific inhibitor SB431542 significantly inhibited the regulatory role of UC-MSC on Treg cells in SLE patients. Immune microenvironment in SLE patients can significantly stimulate the TGF-β1 expression on UC-MSC and plays an important role in the up-regulation of Treg cells in patients.

THE REGULATORY T-LYMPHOCYTES IMMUNOSUPPRESSOR EFFECTS OF BLOOD UNDER DISSEMINATED PULMONARY TUBERCULOSIS WITH MULTI-DRUG RESISTANT M. TUBERCULOSIS

The work analyzed subpopulation structure of peripheral blood T-regulatory cells (T-reg) and production of cytokines with immunosuppressor activity (IL-10, TGF-b) in vitro in patients with disseminated pulmonary tuberculosis, depending on the sensitivity of Mycobacterium tuberculosis to anti-tuberculosis drugs. It has been shown that Trn – natural T-regulatory lymphocytes (CD4 + CD25 + Foxр3 + ) and TGF-b cytokine, formed by them, play the leading role in the formation of immunosuppression under disseminated pulmonary tuberculosis. Besides, subpopulation imbalance of Treg-cells in patients with disseminated pulmonary tuberculosis, in case at multi-drug-resistance and drug-susceptible, is shown by the increased content of T-reg-cells with CD4 + CD25 + Foxр3 + phenotypein combination with the deficiency of CD4 + CD25 + Foxр3 – T-reg lymphocytes in blood. The increase in the amount of CD4 + CD25 + Foxр3 + T-reg-cells in blood of patients with disseminated multi-drug resistance pulmonary tuberculosis is associated with the increase in basal and BCG-induced production of TGF-b in vitro .

Study of Regulatory T-Cells in Patients with Gastric Malt Lymphoma: Influence on Treatment Response and Outcome

PurposeFOXP3+ regulatory T cells (Treg) play an essential role in modulating host responses to tumors and infections. The role of these cells in the pathogenesis of MALT lymphomas remains unknown. The aims of the study were to quantify the number of infiltrating FOXP3+ and CD3+ cells in patients with gastric MALT lymphoma at diagnosis and to study kinetics of these cells and CD20+ tumor cells after treatment and during long-term follow-up.MethodsFOXP3+, CD3+ and CD20+ cells were analyzed by immunohistochemistry and the number of cells was quantified using a micrometric ocular. Samples of 35 patients with gastric MALT lymphoma at diagnosis and after treatment were included. Diagnostic samples were compared to 19 cases of chronic gastritis and diffuse large B-cell lymphoma (DLBCL) of the stomach.ResultsThe median number of FOXP3+ infiltrating cells was higher (27 cells/cm2) in gastric MALT patients than in DLBCL (10 cells; p = 0.162) but similar to chronic gastritis (20 cells; p = 0.605). No characteristic or specific distribution pattern of infiltrating FOXP3+ cells was found. Gastric MALT lymphoma patients responding to bacterial eradication therapy had higher number of FOXP3+ cells at study entry. Kinetics of both infiltrating FOXP3+ cells and tumor CD20+ cells were strongly dependent on the treatment administered.DiscussionGastric MALT lymphomas have a number of Treg cells more similar to chronic gastritis than to DLBCL. Patients with higher number of tumor infiltrating FOXP3+ cells at study entry seem to have better response to antibiotics. Kinetics of Treg and tumor cells are influenced by type of treatment.

CVID patients with autoimmunity have elevated T cell expression of granzyme B and HLA-DR and reduced levels of Treg cells

AimsCommon variable immunodeficiency (CVID) is a primary antibody immunodeficiency with approximately 20% of patients reporting additional autoimmune symptoms. The primary aim of this study was to compare the levels of...

Modulation of STAT‐3 in rheumatoid synovial T cells suppresses Th17 differentiation and increases the proportion of Treg cells

To investigate the impact of STAT-3-mediated regulation on Th17 differentiation in patients with rheumatoid arthritis (RA). CD4+ T cells isolated from peripheral blood (PB) and synovial fluid (SF) were stimulated to differentiate into Th17 cells or Treg cells. The activity of STAT-3 was knocked down by transfecting CD4+ T cells with small interfering RNA (siRNA). After 3 days in culture, the proportions of Th17 cells and Treg cells were measured by flow cytometry, and the production of interleukin-17 (IL-17) was measured by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The levels of IL-17, IL-6, IL-23, IL-1, and tumor necrosis factor α were significantly higher in RA SF and synovial tissue than in SF and synovial tissue from osteoarthritis patients. In RA synovial tissue, the expression of STAT-3 increased in proportion to the severity of synovitis, as shown by stromal cellularity, intimal hyperplasia, and inflammatory infiltration. The degree of Th17 differentiation was highest in RA SF, followed by RA PB, and lowest in normal subjects. In CD4+ T cells, transfection with STAT-3 siRNA prevented Th17 differentiation of mononuclear cells from RA PB and SF but increased the proportion of Treg cells. In contrast, inhibition of STAT-5, the transcription factor for Treg cells, increased the proportion of Th17 cells and reduced that of Treg cells. Our findings indicate that modulation of STAT-3 in CD4+ T cells affects the differentiation of Th17 cells and Treg cells in patients with RA. This role of STAT-3 in RA synovial T cells may provide a new therapeutic target for the management of RA.

Brief Report: Inhibition of interleukin‐6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis

From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA. Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg). Compared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients. This study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA.

OC-067 The balance between t helper 17 and FOXP3+ T regulatory cells in patients with chronic hepatitis C: relation to disease activity and hepatic fibrosis

IntroductionT helper (Th)17 cells, a newly identified subset of Th cells, are major mediators of inflammation-associated disease and have a reciprocal developmental relationship with the immunosuppressive T regulatory (Treg) cells,...

A shorter time to the first treatment may be predicted by the absolute number of regulatory T‐cells in patients with Rai stage 0 chronic lymphocytic leukemia

Regulatory T-cells (Tregs) are increased in chronic lymphocytic leukemia(CLL) and correlates with clinical and biological features of active/progressive disease. However, little is known about their ability to predict the time to first treatment (TFT). We evaluated 75 patients with Rai stage 0 CLL, in whom the absolute number of Tregs was determined at diagnosis, and correlated to main clinical and biological features, as well as to the need of receiving any specific therapy during the course of the disease. After a median follow-up of 30 months, 12 patients(16%) required therapy at some time from the diagnosis. Treated patients showed a significant higher number of peripheral white blood cells and B-lymphocytes, platelet count, cases with unmutated immunoglobulin heavy chain status, and high-risk cytogenetic abnormalities,as well as lower hemoglobin values, than patients who did not need therapy. A greater number of circulating Tregs was detected in treated patients (P < 0.001). Multivariate analysis confirmed that the absolute number of Tregs was an independent predictor of TFT in these patients, the best predictive cut-off being 41/mL. These data show that the absolute Tregs cell number is able to identify Rai stage 0 CLL patients at higher risk of requiring therapy.