Treatment of Graves’ disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes

Pathogenic mechanisms underlying the development of systemic lupus erythematosus (SLE) are very complex and not yet entirely clarified. However, the pivotal role of T lymphocytes in the induction and perpetuation of aberrant immune response is well established. Among T cells, IL-17 producing T helper (Th17) cells and regulatory T (Treg) cells represent an intriguing issue to be addressed in SLE pathogenesis, since an imbalance between the two subsets has been observed in the course of the disease. Treg cells appear to be impaired and therefore unable to counteract autoreactive T lymphocytes. Conversely, Th17 cells accumulate in target organs contributing to local IL-17 production and eventually tissue damage. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent an intriguing and useful tool for SLE treatment in the next future. In this paper, the current knowledge about Treg and Th17 cells interplay in SLE will be discussed.

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Function and expression of checkpoint inhibitors and immune agonists on immune cells in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM and tumor-specific T lymphocytes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11577 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11577-11577 ◽

Cited By ~ 1

Author(s):

Jooeun Bae ◽

Brandon Nguyen ◽

Yu-Tzu Tai ◽

Teru Hideshima ◽

Dharminder Chauhan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Suppressor Cells ◽

Treg Cells ◽

T Cell Subsets ◽

Direct Stimulation ◽

Novel Therapeutic Strategies

11577 Background: Characterization of expression and function of immune regulatory molecules in tumor microenvironment will provide the framework for developing novel therapeutic strategies. Methods: We evaluated the expression and functional impact of various immuno-regulatory molecules, PD-1, PDL-1, PDL-2, LAG3, TIM3, OX40 and GITR, on the CD138+ tumor cells, myeloid derived suppressor cells (MDSC), and T cell subsets from patients with MGUS, SMM and active MM (newly diagnosed, relapsed, relapsed/refractory), and the myeloma-specific cytotoxic T lymphocytes (CTL) induced with XBP1/CD138/CS1 peptides. Results: PDL-1/PDL-2 was more highly expressed on CD138+ myeloma cells in active MM than SMM or MGUS. G-type MDSC (CD11b+CD33+HLA-DRlowCD15+). Treg cells (CD3+CD4+/CD25+FOXP3+) numbers were increased and expressed higher levels of PD1/PD-L1 in active MM than in MGUS, SMM or healthy donors. Among the checkpoint molecules (PD-1, PDL-1, PDL-2, LAG3, OX40, GITR) evaluated, PD-1 showed the highest expression on CD3+CD4+ and CD3+CD8+T cells in BMMC and PBMC from patients with active MM. Functionally, T cells from MM patients showed increased proliferation upon treatment with an individual immune agonist ( > 150%) or checkpoint inhibitor ( > 100%). Interestingly, each individual anti-checkpoint molecule induced proliferation of T cells expressing other checkpoint molecules. In addition, the blockade of PD1, LAG3 or TIM3 enhanced MM antigen-specific cytotoxicity, assessed by parameters including CD107a, granzyme B and IFN-g production, which was most prominent within the memory CTL subset of MM antigen-specific T cells. Conclusions: These results demonstrate an increased frequency of immune regulatory cells, which highly express checkpoint inhibitors in active MM. Direct stimulation with an immune agonist or blockade of a checkpoint inhibitor increased MM patients’ T cell proliferation and myeloma-specific CTL function, supporting development of combination immune regulatory therapies to improve patient outcome in MM.

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Molecular analysis of antigen receptor variable region repertoires in T lymphocytes infiltrating the intrathyroidal and extrathyroidal manifestations in patients with Graves' disease*

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0029-1211709 ◽

2009 ◽

Vol 104 (S 04) ◽

pp. 84-87 ◽

Cited By ~ 1

Author(s):

A. E. Heufelder ◽

H.-D. Schworm ◽

B. E. Wenzel ◽

J. A. Garrity ◽

Rebecca S. Bahn

Keyword(s):

T Lymphocytes ◽

Molecular Analysis ◽

Antigen Receptor ◽

Variable Region ◽

Graves Disease

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Decreased Frequencies of Peripheral Blood CD4+CD25+CD127–Foxp3+ in Patients with Graves’ Disease and Graves’ Orbitopathy: Enhancing Effect of Insulin Growth Factor-1 on Treg Cells

Hormone and Metabolic Research ◽

10.1055/s-0042-122780 ◽

2017 ◽

Vol 49 (03) ◽

pp. 185-191 ◽

Cited By ~ 4

Author(s):

Przemyslaw Pawlowski ◽

Kamil Grubczak ◽

Jerzy Kostecki ◽

Elzbieta Ilendo-Poskrobko ◽

Marcin Moniuszko ◽

...

Keyword(s):

Growth Factor ◽

Peripheral Blood ◽

Treg Cells ◽

Graves Disease ◽

Enhancing Effect ◽

Insulin Growth Factor ◽

Graves Orbitopathy

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T-lymphocytes phenotypic composition of peripheral blood in patients with Graves’ disease undergoing conservative therapy with thiamazole

Problems of Endocrinology ◽

10.14341/probl12812 ◽

2021 ◽

Vol 67 (6) ◽

pp. 39-49

Author(s):

M. A. Dudina ◽

S. A. Dogadin ◽

A. A. Savchenko ◽

V. D. Belenyuk

Keyword(s):

T Lymphocytes ◽

Peripheral Blood ◽

Controlled Trial ◽

Effective Control ◽

Control Group ◽

Direct Immunofluorescence ◽

Graves Disease ◽

Open Label ◽

T Helpers

BACKGROUND: Effective control of autoimmune inflammation in Graves’ disease determines necessity to study the T helper (Th) and cytotoxic T-lymphocytes dysfunction, as well as the level of regulatory T-cells (Treg) activation in patients with Graves’ disease on thyrostatic medication, which will clarify the immunomodulatory effects of long-term thiamazole treatment serve as targets for more specific therapies.AIM: To study the phenotypic composition of T-lymphocytes in the peripheral blood of patients with Graves’ disease to assess the direction of immune response depending on thimazole-induced euthyroidism duration.MATERIALS AND METHODS: A single-center, cohort, continuous, open-label, controlled trial was conducted to assess the phenotypic composition of T-lymphocytes in peripheral blood in women with Graves’ disease on long-term thiamazole treatment. The phenotypic composition of T-lymphocytes was determined by flow cytometry using direct immunofluorescence with conjugated FITC monoclonal antibodies depending on the duration of thimazole-induced euthyroidism of long-term thiamazole treatment.RESULTS: The study included 135 women with Graves’ disease, mean age 43.09±12.81 years, 120 (88.91%) with a relapse of the disease and 15 (11.09%) with newly diagnosed hyperthyroidism. An increase of activated CD3+CD4+CD25+ was found in patients with Graves’ disease with a duration of thimazole-induced euthyroidism 5–8 months and 9–12 months, respectively, Me=0.94 (0.48–1.45), p=0.020) and Me=0.95 (0.41–1.80), p=0.025), in control group — Me=0.12 (0.03–0.68). Compared to the control an increase of CD4+CD25+CD127Low (Treg) was found in patients with a duration of thimazole-induced euthyroidism 5–8 and 9–12 months. The content of Treg in peripheral blood in Graves’ disease patients with a duration of thimazole-induced euthyroidism more than 12 months decreases, but remains elevated relative to the control.CONCLUSION: In patients with Graves’ disease with a duration of thimazole-induced euthyroidism 5–8 months and 9–12 months the level of Treg has been increased. The increase of activated Th (CD3+CD4+CD25+) persists independently of thimazole-induced euthyroidism. In patients with Graves’ disease with a duration of thimazole-induced euthyroidism for more than 12 months, there is a compensatory increase in regulatory T-lymphocyte, and the total number of T-helpers is restored to the control.

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PD-1/PD-L1 immune check points blockade to attenuate growth of metastatic colon cancer in the CBP/β-catenin inhibited liver.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.556 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 556-556

Author(s):

Kiminori Kimura ◽

Yosuke Osawa ◽

Koji Nishikawa ◽

Masamichi Kimura ◽

Yutaka Kawakami

Keyword(s):

Colon Cancer ◽

Liver Metastasis ◽

T Lymphocytes ◽

Liver Tumors ◽

Survival Rates ◽

Treg Cells ◽

Metastatic Colon Cancer ◽

Cytokines And Chemokines ◽

Check Points ◽

Immune Check Points

556 Background: Immune check points blockade with specific antibodies can accelerate anti-tumor immunity, resulting in a clinical response in patients with various types of cancer. Thus, a wide variety of treatment combinations based on PD-L1/ PD-1 pathway blockage are under development to enhance the therapeutic effect. Here, the effects of the combination treatment of PRI-724, a selective inhibitor of the CBP/β-catenin, with anti-PD-L1 antibody were examined in a mouse model of the liver metastasis of colon cancer. Methods: Mice were inoculated with SL4 colon cancer cells into the spleen to produce metastatic liver tumors. The animals were intraperitoneally injected with or without PRI-724 and/or anti-PD-L1 antibody (10F.9G2) 3 times a week. A part of mice treated with PRI-724 and anti-PD-L1 antibody was administrated with anti-mouse CD4 or CD8 antibody 3 times a week. First, to evaluate anti-tumor effect in those mice, we analyzed liver histology and survival rates after treatment. Next, to examine immune response in the liver, intrahepatic lymphocytes were analyzed by FACS for CD8 memory phenotype, Treg cells, macrophages, and dendritic cells, and the cytokine production from these cells (TNFa, IFNg etc.). Furthermore, inflammatory cytokines and chemokines mRNAs levels and PCR array concerned to Wnt signaling in the liver and serum cytokines levels were also analyzed. Results: The combination of the treatments resulted in regression of tumor growth, whereas monotherapy of each treatment did not show any anti-tumor activity. PRI-724 increased T lymphocytes recruitment, including CD8+ T cells, in the tumor, which may have been induced by inflammatory chemokines and a change of the macrophage property to the cytotoxic phenotype in the liver. Anti-PD-L1 antibody induced CD69+-activated T lymphocytes in the PRI-724-treated livers of mice inoculated with SL4. Administration of anti-CD8 antibody canceled the anti-tumor effects of the combination treatments of PRI-724 and anti-PD-L1 antibody. Conclusions: Targeting CBP/β-catenin combined with PD-1/PD-L1 immune check points blockade shows potential as a new therapeutic strategy for treating the liver metastasis of colon cancer.

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Increase in inflammatory T cell subsets in atrial fibrillation: the missing link underlying inflammation in AF

European Heart Journal ◽

10.1093/ehjci/ehaa946.3692 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

I.E Dumitriu ◽

P Dimou ◽

S Kaur ◽

S Dinkla ◽

J.C Kaski ◽

...

Keyword(s):

Atrial Fibrillation ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Inflammatory Cytokines ◽

T Lymphocyte ◽

Treg Cells ◽

Funding Source ◽

Functional Assays

Abstract Background The precise role of inflammation in the development and perpetuation of atrial fibrillation (AF) is yet to be fully uncovered. T lymphocytes have pivotal roles in orchestrating inflammation. Specialised subsets of lymphocytes either promote or prevent inflammation. We are investigating a unique subset of lymphocytes, the CD4+CD28null T cells that expand in patients with chronic inflammation. These cells secrete high levels of pro-inflammatory cytokines and have cytolytic function. CD4+CD28null T cells are normally maintained under control by regulatory T cells (Treg), a specialised subset of T lymphocytes with suppressive function that maintain immune homeostasis and prevent pathogenic immune responses. The role of CD4+CD28null and Treg cells has not been investigated in AF. Purpose We hypothesised that in AF the balance between pro-inflammatory and regulatory T lymphocytes is skewed in favour of inflammatory T cells, which may sustain inflammation in AF. Methods Circulating CD4+CD28null T lymphocytes and Tregs were quantified by flow cytometry in paroxysmal and persistent AF patients and healthy controls (n=30). Inflammatory cytokines were quantified in serum and the function of T lymphocyte subsets was investigated using ex vivo functional assays. Results CD4+CD28null T lymphocytes were significantly increased in the circulation of AF patients compared to controls. Of note, a higher proportion of patients with persistent AF showed an increase in inflammatory CD4+CD28null T lymphocytes compared to patients with paroxysmal AF. A marked reduction in Treg cells was present in AF patients compared to controls. Functional assays showed that IL-7 and IL-15 cytokines were responsible for CD4+CD28null T lymphocyte expansion in AF patients. Conclusions We show that patients with AF have marked changes in T lymphocytes subsets: pro-inflammatory CD4+CD28null T cells increase significantly, whilst anti-inflammatory Tregs are significantly reduced. We show for the first time that the cytokines IL-7 and IL-15 are the main drivers of CD4+CD28null T cell expansion in AF patients. These novel findings may reveal novel therapeutic strategies (e.g. cytokine blockade) to re-establish the balance between pro- and anti-inflammatory mechanisms at work in AF to improve patient outcomes. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

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Regulatory T Cells Enhance the Allogeneic Activity of Endothelial-Specific Cytotoxic T Lymphocytes – Protective Effect of Defibrotide

Blood ◽

10.1182/blood.v118.21.4693.4693 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4693-4693

Author(s):

Guenther Eissner ◽

Isabel Hartmann ◽

Altug Kesikli ◽

Silvia Haffner ◽

Tanja Sax ◽

...

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Endothelial Cell ◽

T Cell ◽

T Lymphocytes ◽

Treg Cell ◽

Interleukin 2 ◽

Treg Cells ◽

Protective Function ◽

Phenotypic Quality

Abstract Abstract 4693 BACKGROUND: Damage to the vascular endothelium is the primary event of transplant related complications and often precedes loss of organ function. Depending on the amount of co-stimulatory signals, endothelial cells can either act as stimulating or inhibiting antigen presenting cells (APC). On the other hand, numerous data indicate that CD4+CD25+FoxP3+ T cells (Treg cells) can attenuate alloresponses of conventional T lymphocytes against classical APC and thus qualify for clinical use in various transplant settings. However, it is unknown whether Treg cells also influence T cell – endothelial cell interactions. Defibrotide (DF) is a polydisperse mixture of single-stranded deoxyribonucleotides with anti-thrombotic and anti-inflammatory activity, known to modulate the antigenicity of vascular endothelial cells. METHODS: CD8+ T lymphocytes (CTL) were isolated by magnetic microbead separation of peripheral blood mononuclear cells (PBMC) from healthy human blood donors and stimulated with mito-inactivated cells of a human microvascular endothelial cell line (CDC/EU.HMEC-1, further referred to as EC) and other primary and transformed micro- and macrovascular ECs for 7 days in the presence of interleukin 2 (IL-2). Treg cells from the CTL donor were prepared by CD4 (untouched) and a double CD25 microbead separation as well as a CD127bright depletion, followed by anti-CD3/CD28 expansion in the presence of IL-2 and a phenotypic quality control. Treg cells were added to the CTL-EC co-culture (1:1:1) prior to 51Cr release or flow cytometric cytotoxicity assays. Additionally, Treg cells were also tested for their capacity to influence CTL lysis of Epstein-Barr-Virus-transformed B-LCL, which as classical APC were HLA-matched to the HMEC. Furthermore, EC targets were incubated in the presence or absence of DF (25μM) for 24 hrs to assess the drug's protective function on the allogenicity of EC. RESULTS: EC-stimulated CTL showed a specific MHC class I-restricted target lysis. Addition of Treg cells prior to the cytotoxicity assay and during the afferent immune phase surprisingly increased EC lysis by CTL. In contrast, Treg cells alone did not show any lytic activity against EC. As a control, conventional CD4+CD25- T cells did not influence CTL activity either. Treg cell-mediated enhancement was endothelial-specific, since B-LCL lysis was not influenced. Further subpopulation analysis revealed the existence of CD8+/CD28-/CD57+ CTL, requiring cell-to-cell contact with Treg cells for their increased activity towards EC. Importantly, DF could almost fully protect EC against lysis by allogeneic CD28- CTL and the Treg cell-mediated enhancement. Of note, DF exclusively protected EC and did influence T cell function nor viability, suggesting a strong tropism for the endothelial cell type. CONCLUSION: There is no doubt about the potential therapeutic efficacy of Treg cells to ameliorate outcome of allogeneic transplants, but the endothelium might require additional protective interventions to prevent specific alloreactivity, such as DF. Disclosures: Eissner: Gentium, Sp.A.: Consultancy. Iacobelli:Gentium SpA: Employment.

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Advances in Understanding the Immune Imbalance between T-Lymphocyte Subsets and NK Cells in Recurrent Spontaneous Abortion

Geburtshilfe und Frauenheilkunde ◽

10.1055/a-0634-1813 ◽

2018 ◽

Vol 78 (07) ◽

pp. 677-683 ◽

Cited By ~ 13

Author(s):

Xiaoxuan Zhao ◽

Yuepeng Jiang ◽

Lin Wang ◽

Zhihao Li ◽

Qiang Li ◽

...

Keyword(s):

T Lymphocytes ◽

Nk Cells ◽

Spontaneous Abortion ◽

Nk Cell ◽

Treg Cells ◽

Recurrent Spontaneous Abortion ◽

T Lymphocyte Subsets ◽

Cell Dysfunction ◽

Regulatory T Lymphocytes ◽

Immune Imbalance

AbstractRecurrent spontaneous abortion is a global problem, and unexplained recurrent abortion triggered by immunological factors is an important focus of current research. Helper T lymphocytes (Th cells) and regulatory T lymphocytes (Treg cells) are central in human immune regulation and play a complex role in pregnancy. Natural killer cells (NK cells) exist in the endometrium and cooperate with T lymphocytes to create immune tolerance at the maternal-fetal interface, which is essential for successful pregnancy. This review has analyzed studies on Th17 cell, Treg cell and NK cell dysfunction and cellular imbalances which may contribute to unexplained recurrent spontaneous abortion to suggest a possible direction for future immunotherapies.

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