Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
T cell growth factor [keywords]
- Continuous requirement for the TCR in regulatory T cell function. [JOURNAL ARTICLE]
- Nat Immunol 2014 Sep 28.
Foxp3(+) regulatory T cells (Treg cells) maintain immunological tolerance, and their deficiency results in fatal multiorgan autoimmunity. Although heightened signaling via the T cell antigen receptor (TCR) is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrated that inducible ablation of the TCR resulted in Treg cell dysfunction that could not be attributed to impaired expression of the transcription factor Foxp3, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2 (IL-2). Instead, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in the suppressor capacity of Treg cells.
- Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening. [Journal Article]
- Int J Hypertens 2014.:126365.
Adaptive immune function is implicated in the pathogenesis of vascular disease. Inhibition of T-lymphocyte function has been shown to reduce hypertension, target-organ damage, and vascular stiffness. To study the role of immune inhibitory cells, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), on vascular stiffness, we stimulated the proliferation of Treg lymphocytes in vivo using a novel cytokine immune complex of Interleukin-2 (IL-2) and anti-IL-2 monoclonal antibody clone JES6-1 (mAbCD25). Three-month-old male C57BL/6J mice were treated with IL-2/mAbCD25 concomitantly with continuous infusion of angiotensin type 1 receptor agonist, [Val(5)]angiotensin II. Our results indicate that the IL-2/mAbCD25 complex effectively induced Treg phenotype expansion by 5-fold in the spleens with minimal effects on total CD4(+) and CD8(+) T-lymphocyte numbers. The IL-2/mAbCD25 complex inhibited angiotensin II-mediated aortic collagen remodeling and the resulting stiffening, analyzed with in vivo pulse wave velocity and effective Young's modulus. Furthermore, the IL-2/mAbCD25 complex suppressed angiotensin II-mediated Th17 responses in the lymphoid organs and reduced gene expression of IL-17 as well as T cell and macrophage infiltrates in the aortic tissue. This study provides data that support the protective roles of Tregs in vascular stiffening and highlights the use of the IL-2/mAbCD25 complex as a new potential therapy in angiotensin II-related vascular diseases.
- Comparison of pro-inflammatory cytokines among patients with bipolar disorder and unipolar depression and normal controls. [JOURNAL ARTICLE]
- Bipolar Disord 2014 Sep 25.
Research evidence has shown that bipolar disorder (BD) and unipolar depression (UD) are both related to inflammatory dysregulation, but few studies have compared the levels of cytokines between these two disorders.Study subjects were age- and gender-matched outpatients with BD or UD and normal controls (NC). Severities of depression and mania symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Pro-inflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1), soluble p-selectin receptor (sP-selectin), and monocyte chemotactic protein-1 (MCP-1), were assessed in all subjects by enzyme-linked immunosorbent assays.In all, 130 patients with BD, 149 patients with UD, and 130 NC were enrolled in the study; 67.6% were female and the average age was mean ± standard deviation (SD) 43.5 ± 11.8 years. The BD group had a significantly higher smoking rate, more medical comorbidity, higher body mass index (BMI), and higher levels of sIL-2R, sIL-6R, CRP, sTNF-R1, and MCP-1 (all p < 0.01) than the UD and NC groups. When the remitted patients with BD (YMRS scores ≤ 12) were compared with the patients with UD, controlling for age, MADRS score, smoking, medical comorbidity, and BMI in the regression model, the results showed that the BD group had significantly higher levels of sIL-6R (p < 0.001), CRP (p = 0.045), sTNF-R1 (p = 0.036), and MCP-1 (p = 0.001) than the UD group.Higher levels of sIL-6R, CRP, sTNF-R1, and MCP-1 were noted in BD than in UD. These results may suggest a more severe inflammatory dysregulation in BD. Further studies are required to investigate whether these cytokines could be biomarkers for affective disorders.
- Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 favours sustained lymphocyte recovery in acute myeloid leukemia. [LETTER]
- Eur J Haematol 2014 Sep 25.
The recent contribution by Michelis et al. convincingly shows that an early recovery of lymphocytes in blood following allogeneic hematopoietic cell transplantation heralds a reduced risk of relapse for patients with acute myeloid leukemia (AML) (1). In a multicenter phase III trial (n=320), post-consolidation therapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) was found to significantly prevent relapse of AML, as accounted for in detail elsewhere (2). Immunotherapy with HDC/IL-2 aims to mimic the graft-versus-leukemia reaction achieved by allogeneic transplantation by optimally expanding and activating natural killer cells and T cells (3). This article is protected by copyright. All rights reserved.
- Fever-Range Whole-Body Heat Treatment Stimulates Antigen-Specific T-Cell Responses in Humans. [JOURNAL ARTICLE]
- Immunol Lett 2014 Sep 22.
Increase in body temperature has been thought to play an important role in the regulation of immune responses, although its precise mechanisms are still under investigation. Here, we examined the effects of physiologically relevant thermal stress on the cytokine production from human peripheral T cells. Volunteers were heated using a whole-body hyperthermia device, the rectal temperature was maintained above 38.5°C for more than 60min, and peripheral blood mononuclear cells (PBMCs) were obtained before and after the treatment. When T cells were stimulated with anti-CD3/CD28 antibodies, marked increases in the production of interferon-γ (IFN-γ) and interleukin-2 were observed in PBMCs prepared immediately after and 24h after the treatment. Similarly, enhanced production of IFN-γ in response to the tuberculin purified protein derivative or antigenic viral peptides was also observed immediately after and 24h after the treatment. Fluorescence photo-bleaching analyses showed heat-induced increase of membrane fluidity in T cells, which probably enables them to induce rapid and efficient cluster formation of molecules involved in antigen recognition and signal transduction for T-cell stimulation. We concluded that physiologically relevant thermal stress could efficiently modify T-cell responsiveness to various stimuli, including enhanced responses to specific antigens.
- Polysaccharides from Cymbopogon citratus with antitumor and immunomodulatory activity. [JOURNAL ARTICLE]
- Pharm Biol 2014 Sep 26.:1-8.
Abstract Context: Most of the present studies on the antitumor efficiency of Cymbopogon citratus (DC.) Stapf (Gramineae) are limited to its low-mass compounds, and little information about the antitumor activity of polysaccharides from this plant is available. Objectives: This study focused on the potential antitumor and immunomodulatory activities of polysaccharides (CCPS) from C. citratus. Materials and methods: CCPS was isolated using the water extraction-ethanol precipitation method. The sarcoma 180 (S180) cells-inoculated mice were intraperitoneally administrated with CCPS (30-200 mg/kg/d) for seven consecutive days. The effects of CCPS on tumor growth, thymus and spleen weights, splenocyte proliferation, and cytokine secretion in the tumor-bearing mice were measured. The cytotoxicity of CCPS (50-800 μg/mL) towards S180 cells was also studied. Results: CCPS significantly inhibited the growth of the transplanted S180 tumors, with the inhibition rates ranging from 14.8 to 37.8%. Simultaneously, CCPS dose-dependently improved the immunity of the tumor-bearing mice. With the highest dose of 200 mg/kg/d, the thymus and spleen indices were increased by 21.9 and 91.9%, respectively; ConA- and LSP-induced splenocyte proliferations were increased by 32.7 and 35.3%, respectively. The secretions of interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 2 (IL-12), and tumor necrosis factor-α (TNF-α) were increased by 103.2, 40.2, 23.6, and 26.3%, respectively. Nevertheless, almost no toxicity of CCPS towards S180 cells was observed, with the maximal inhibition rate less than 15% at the CCPS concentration of 800 μg/mL. Conclusion: CCPS exhibited antitumor activity in vivo, and this activity might be achieved by immunoenhancement rather than direct cytotoxicity.
- Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE patients. [JOURNAL ARTICLE]
- Lupus 2014 Sep 24.
MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.
- Optimizations of SiRNA Design for the Activation of Gene Transcription by Targeting the TATA-Box Motif. [JOURNAL ARTICLE]
- PLoS One 2014; 9(9):e108253.
Small interfering RNAs (siRNAs) are widely used to repress gene expression by targeting mRNAs. Some reports reveal that siRNAs can also activate or inhibit gene expression through targeting the gene promoters. Our group has found that microRNAs (miRNAs) could activate gene transcription via interaction with the TATA-box motif in gene promoters. To investigate whether siRNA targeting the same region could upregulate the promoter activity, we test the activating efficiency of siRNAs targeting the TATA-box motif of 16 genes and perform a systematic analysis to identify the common features of the functional siRNAs for effective activation of gene promoters. Further, we try various modifications to improve the activating efficiency of siRNAs and find that it is quite useful to design the promoter-targeting activating siRNA by following several rules such as (a) complementary to the TATA-box-centered region; (b) UA usage at the first two bases of the antisense strand; (c) twenty-three nucleotides (nts) in length; (d) 2'-O-Methyl (2'-OMe) modification at the 3' terminus of the antisense strand; (e) avoiding mismatches at the 3' end of the antisense strand. The optimized activating siRNAs potently enhance the expression of interleukin-2 (IL-2) gene in human and mouse primary CD4+ T cells with a long-time effect. Taken together, our study provides a guideline for rational design the promoter-targeting siRNA to sequence-specifically enhance gene expression.
- Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. [JOURNAL ARTICLE]
- Cancer 2014 Sep 23.
Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma.Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded.Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition.RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule. Cancer 2014. © 2014 American Cancer Society.
- Characterisation of a K390R ITK Kinase Dead Transgenic Mouse - Implications for ITK as a Therapeutic Target. [JOURNAL ARTICLE]
- PLoS One 2014; 9(9):e107490.
Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells and this has prompted significant efforts to discover ITK inhibitors for the treatment of allergic disease. However, ITK is known to have functions outside of its kinase domain and in general kinase knockouts are often not good models for the behaviour of small molecule inhibitors. Consequently we have developed a transgenic mouse where the wild type Itk allele has been replaced by a kinase dead Itk allele containing an inactivating K390R point mutation (Itk-KD mice). We have characterised the immune phenotype of these naive mice and their responses to airway inflammation. Unlike Itk knockout (Itk-/-) mice, T-cells from Itk-KD mice can polymerise actin in response to CD3 activation. The lymph nodes from Itk-KD mice showed more prominent germinal centres than wild type mice and serum antibody levels were significantly abnormal. Unlike the Itk-/-, γδ T cells in the spleens of the Itk-KD mice had an impaired ability to secrete Th2 cytokines in response to anti-CD3 stimulation whilst the expression of ICOS was not significantly different to wild type. However ICOS expression is markedly increased on αβCD3+ cells from the spleens of naïve Itk-KD compared to WT mice. The Itk-KD mice were largely protected from inflammatory symptoms in an Ovalbumin model of airway inflammation. Consequently, our studies have revealed many similarities but some differences between Itk-/-and Itk-KD transgenic mice. The abnormal antibody response and enhanced ICOS expression on CD3+ cells has implications for the consideration of ITK as a therapeutic target.