T-helper Cell Type Research Articles

Registries for paediatric pulmonary hypertension

Background: T-helper cell type 2 lymphocytes (Th2) play an important role in initiation, progression and persistence of asthma. An increase in Th2 cells activity in asthma may be due to a reduction in T-regulatory cells (nTreg) that normally inhibit Th2 cells. Objective: The aim of this study was to reveal the association between T-regulatory cells blood content and cytokines production by Th1 and Th2 cells in patients with asthma. Methods: 81 patients with asthma and 30 matched control subjects were included. All underwent clinical examination and spirometry. Investigation of nTreg in blood was carried out by flow cytometry. nTreg were defined as a fraction of CD4+CD25+-lymphocytes with a high level of CD25 expression (CD4+CD25hi-cells). IFN-γ and IL-4 cytokines concentration in blood was assessed by enzyme immunoassay. Results: Patients with asthma had significantly lower values of CD4+CD25hi-cells than controls (5,38 (2,84-6,59)% vs 7,40 (6,41-8,52)%; p Conclusion: Decrease of T-regulatory cells blood content in asthma is associated with increased functional activity of Th2 cells (increased IL-4 production, decreased IFN-γ/IL-4 ratio) and both these parameters are linked to disease severity.

Alterations in the Cellular Immune Compartment of Patients Treated with Third-Party Mesenchymal Stromal Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

Adoptive transfer of third-party mesenchymal stromal cells (MSCs) has emerged as a promising tool for the treatment of steroid-refractory graft-versus-host disease (GVHD). Despite numerous in vitro studies and preclinical models, little is known about their effects on the patients' immune system. We assessed immune alterations in the T-cell, B-cell, natural killer cell, dendritic cell, and monocytic compartments of steroid-refractory GVHD patients 30, 90, and 180 days after MSC (n = 6) or placebo (n = 5) infusion, respectively. Infused MSCs were bioactive as suggested by the significant reduction in epithelial cell death, which represents a biomarker for acute GVHD. There were several indications that MSCs shift the patients' immune system toward a more tolerogenic profile. Most importantly, infusion of MSCs was associated with increased levels of regulatory (forkhead box P3 (FOXP3)(+) and interleukin (IL)-10(+) ) T-cells, reduced pro-inflammatory IL-17(+) T(Th17)-cells, and skewing toward type-2 T-helper cell responses. Furthermore, IL-2, which has been recently shown to exert a positive immune modulating effect in GVHD patients, was higher in the MSC patients at all evaluated time points during 6 months after MSC-infusion. Overall, our findings will contribute to the refinement of monitoring tools, for assessing MSC treatment-efficacy and increase our understanding regarding the MSCs' in vivo effects.

Update in Sepsis 2012

Pivotal sepsis clinical trials and preclinical research in 2012 are reviewed. For interventions ranging from synthetic complex starch solutions to recombinant human activated protein C, large multicenter randomized controlled trials generally failed to show benefit and some even demonstrated harm in the intervention group. In smaller innovative clinical trials simple interventions such as external cooling to control fever and biomarker-guided weaning from mechanical ventilation found potential benefit. Biomarkers for sepsis, including multimarker panels, are increasingly showing promise for clinical application. Breakthroughs in basic research in sepsis continue to highlight the complexity of the systemic inflammatory response and its consequences. A series of publications in AJRCCM follow the septic inflammatory response starting from intracellular structures and organelles to mitochondria and the cytoskeleton. Additional publications explore the key leukocyte subsets acting in sepsis, highlighting the underappreciated role of helper T-cell type 2-related pathways. Cellular remnants in the form of microparticles contribute to coagulopathy and further organ dysfunction. As a consequence, we suggest that sepsis may be the paradigm disease or condition requiring personalized care first to discover and validate new therapies and second to increase survival.

Inflammometry in pediatric asthma: A review of fractional exhaled nitric oxide in clinical practice

The burden of pediatric asthma remains high with one-third of patients being under- or overtreated because of the unique challenges in the assessment and management of childhood asthma. Until recently, there has been no point of care tool for assessing the underlying airway inflammation (i.e., inflammometry) in asthma. Recently, fractional exhaled nitric oxide (FeNO) has emerged as an important biomarker for the assessment and management of asthma. Recent evidence indicates that FeNO identifies T-helper cell type 2 (Th2)–mediated airway inflammation with a high positive and negative predictive value for identifying corticosteroid responsive airway inflammation. This article examines the evidence for FeNO as a predictor of Th2-mediated inhaled corticosteroid (ICS) responsive airway inflammation and reviews recent studies evaluating the role of FeNO, whether helpful or not, in the assessment and management of pediatric asthma. FeNO is a reliable adjunct to traditional tests in the assessment of suspected asthma. Importantly, it is useful for identifying and for excluding ICS-responsive airway inflammation. Although individual study results have varied, collectively, asthma managed using FeNO is associated with lower exacerbation rates compared with clinical algorithms alone. Finally, FeNO may be useful in identifying patients at risk for future impairment or loss of asthma control during reduction/cessation of ICS treatment. FeNO testing has an important role in the assessment of pediatric patients with suspected asthma and in the management of pediatric patients with established asthma. Additional studies will continue to define the exact role of FeNO testing in pediatric asthma.

Schistosomiasis and Impaired Response to Antiretroviral Therapy Among HIV-Infected Patients in Tanzania

Schistosomiasis affects over 230 million people worldwide, 90% of whom live in sub-Saharan Africa(1). Data suggests helminthic infections like schistosomiasis may hasten HIV progression in co-infected patients(2,3). Helminths induce chronic immune activation, shifting from a T-helper cell type 1 (Th1) to type 2 (Th2) immune response. Th2-lymphocytes down-regulate cytotoxic effects of CD8+ T-lymphocytes, leading to an altered cytokine profile with increased viral replication(4–7). Studies have shown that treating ascariasis or filariasis improves CD4+ T-cell counts (CD4 counts) and viral loads in HIV-infected patients(8, 9). Little research has explored the specific interaction between schistosomiasis and HIV, but one study yielded concerning results. Antiretroviral therapy (ART)-naive HIV-infected patients with schistosome co-infection who were randomized to delayed anti-schistosome treatment with praziquantel after three months had larger increases in HIV RNA levels and greater declines in CD4 counts than patients treated immediately(10). Despite this possible interaction, schistosomiasis screening is not currently recommended for HIV-infected patients in many endemic countries, including Tanzania. Also, no study has yet assessed impact of schistosomiasis on ART response. We hypothesized that schistosome infection may adversely affect HIV-infected patients’ responses to ART. We conducted a retrospective cohort study to explore this issue at Bugando Medical Centre (BMC) near Lake Victoria in Tanzania, where schistosomiasis is hyper-endemic.

Subpopulations of helper T lymphocytes in tuberculous pleurisy

Although it is curable, tuberculosis continues to be is a major global public health problem, especially in developing countries. Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis. It has been well documented that CD4(+) T lymphocytes are dominant leukocytes present in TPE. Traditionally, CD4(+) T cells have been classified into two functionally distinct subsets, helper T-cell type 1 (Th1) and Th2 cells, based on their cytokine production profiles. Recently, regulatory T cells, Th17 cells, Th9 cells, and Th22 cells have been added to the 'portfolio' of Th cells. In this review, we summarize recent findings regarding the phenotypic characteristics of the above Th cells, the mechanisms of differentiation and recruitment of Th cells into pleural space, and the immune regulation of Th cells in TPE environment. We also describe the interplay between different Th cells, as well as between Th cells and other type of cells, such as pleural mesothelial cells in TPE. Further studies should be directed at identifying the mediators and mechanisms involved in the immunoregulatory properties of pleural Th cells in tuberculosis infection.

Cytokine Profile in Human Eyes: Contribution of a New Cytokine Combination for Differential Diagnosis between Intraocular Lymphoma or Uveitis

Primary intraocular lymphoma (PIOL), also called primary vitreoretinal lymphomas, often masquerades as uveitis. This misdiagnosis can result in subsequent brain involvement and oculocerebral lymphoma (OCL). In this study, we sought to characterize the helper T-cell type 1 (Th1)/Th2 cytokine profile in vitreous samples from patients with PIOL, OCL, uveitis and controls with non-inflammatory disease. Vitreous and aqueous humor samples from 87 patients with PIOL (n = 30), OCL (n = 12), uveitis (n = 34), and retinal detachment (RD) without hemorrhage (n = 11) were analyzed and their concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were determined by flow cytometric bead arrays (CBA). The IL-10 levels determined by CBA were compared with those by ELISA. IL-10 concentrations measured by CBA and ELISA were highly correlated. IL-2, IL-4, and TNFα were not detected in any sample. The only cytokine detected at a significant level in samples from RD vitreous was IL-6. The IL-10/IL-6 ratio, as previously reported, was slightly higher in PIOL than in uveitis samples, but not for all patients. Cytokine profiles from PIOL and OCL samples did not differ. The combination of the IL-10/IL-6 and IL-10/IFNγ ratios was highly informative for discriminating PIOL/OCL from uveitis samples and for therapeutic follow up of PIOL. This strategy might be very helpful as an initial screening to rule out PIOL in patients thought to have uveitis.

First-in-Human Study of REGN668/SAR231893 (IL-4Rα mAb): Safety, Tolerability and Biomarker Results of a Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Healthy Volunteers

REGN668/SAR231893 (a fully human IL-4Rα mAb) blocks both IL-4 and IL-13 signaling, inhibiting the T-helper cell type 2 immune pathway. Th2 inflammation is implicated in the pathobiology of diseases such as atopic dermatitis and asthma. We describe the safety and pharmacodynamic results from a first-in-human study in healthy volunteers.

Asthma in school‐aged children, it's time to reveal its entities

Asthma in school‐aged children, it's time to reveal its entities

Asthma phenotypes and endotypes

It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. In this review, we discuss the present understanding of different asthma phenotypes and endotypes, and the prospects of personalized medicine for asthma. The recognition of diverse biological backgrounds in which asthma, and particularly severe asthma, can manifest has prompted the search for refined phenotypes and endotypes in asthma. Such appreciation of the heterogeneity in asthma is also prompting clinical trials to focus on specific subgroups of asthma, as demonstrated by the clinical trial of lebrikizumab. Patients with severe asthma have asthma symptoms that are difficult to control, require high dosages of medication, and continue to experience persistent symptoms, asthma exacerbations or airflow obstruction even with aggressive therapy. Although asthma is traditionally viewed as an eosinophilic inflammatory disorder associated with a T-helper cell type 2 (Th2) immune response, recent studies have identified involvement of other effector cells, nonclassical Th2 cytokines and non-Th2 cytokines in severe asthma pathogenesis. Results of several clinical trials of anticytokine antibodies demonstrated the effectiveness of tailoring asthma treatment on the basis of an individual's biology.

The influence of commensal bacteria-derived signals on basophil-associated allergic inflammation

Commensal bacteria that colonize mammalian mucosal surfaces are reported to influence T helper type 2 (TH2) cytokine-dependent inflammation and susceptibility to allergic disease. However, the mechanisms that underlie these observations are only beginning to be understood. We recently utilized studies of murine model systems and atopic patient populations to elucidate a mechanism by which commensal bacteria-derived signals limit serum immunoglobulin E levels, influence basophil development and steady-state circulating basophil populations and regulate basophil-associated TH2 cell responses and allergic inflammation. In this addendum, we summarize the findings of our recent work and other developments in the field, discuss the broader implications of these findings and generate new hypotheses regarding our understanding of host-commensal relationships. These areas of investigation may be applicable to the development of new preventative or therapeutic approaches to reduce the burden of allergic disease.

A bovine whey protein extract can induce the generation of regulatory T cells and shows potential to alleviate asthma symptoms in a murine asthma model

The number of people with asthma has dramatically increased over the past few decades and the cost of care is more than $11·3 billion per year. The use of steroids is the major treatment to control asthma symptoms, but the side effects are often devastating. Seeking new drugs or new strategies to reduce the dose of steroid taken has always been an important task. A bovine whey protein extract (WPE), which is enriched in transforming growth factor-β (TGF-β), has been demonstrated to have the potential for reducing symptoms associated with mild-to-moderate T-helper cell type 1-mediated psoriasis in human subjects. However, whether WPE also has potential for inhibiting T-helper cell type 2 (Th2)-mediated disease remains unclear. In the present study, using a murine asthma model, we found that sensitised mice fed WPE daily, before they were challenged, resulted in reducing airway inflammation, serum ovalbumin-specific IgE, Th2-related cytokine production and airway hyperresponsiveness. Increase in the regulatory T cell (Treg) population in vitro and in vivo was observed when treated with WPE. According to the results from the TGF-β-blocking antibody study, we suggest that TGF-β is the main component that endows WPE with the potential to reduce the generation of Treg. Thus, the present data suggest that WPE has the potential to alleviate the symptoms of asthma by inducing the generation of Treg. Therefore, regular administration of WPE might be potentially beneficial for patients with asthma.

Short cigarette smoke exposure facilitates sensitisation and asthma development in mice

Epidemiological studies indicate that cigarette smoke exposure is a risk factor for increased sensitisation and asthma development. The aim of this study was to examine the impact of cigarette smoke on sensitisation and allergic airway inflammation in response to a low dose of house dust mite (HDM), and to obtain potential mechanistic insights. Mice were exposed to low doses of HDM extract combined with air or cigarette smoke exposure, either during allergen sensitisation or during the development of allergic airway disease. Mice concomitantly exposed to low-dose HDM, combined with cigarette smoke for 3 weeks, demonstrated an asthmatic phenotype with significantly increased airway eosinophilia, goblet cell metaplasia, airway hyperresponsiveness and a rise in HDM-specific serum immunoglobulin G1, compared to sole HDM or cigarette smoke exposure. In addition, short cigarette smoke inhalation, during the initial contact with HDM allergens, was sufficient to facilitate sensitisation and development of a complete asthmatic phenotype after rechallenge with HDM. Mechanistically, short cigarette smoke exposure amplified dendritic cell-mediated transport of fluorescein isothiocyanate-labelled HDM allergens to the intrathoracic lymph nodes and generated a local T-helper cell type 2 response. Short cigarette smoke exposure is sufficient to facilitate allergic sensitisation and the development of low-dose HDM-induced allergic asthma, possibly by affecting dendritic cell function.

The CD4/CD8 Ratio in Vitreous Fluid Is of High Diagnostic Value in Sarcoidosis

Sarcoidosis is an idiopathic inflammatory disorder involving multiple organs, and ocular manifestation (represented by granulomatous uveitis) is one of the common features. A well-known immunologic feature in sarcoidosis is an increased CD4+ helper T-cell type 1 lymphocyte subset in bronchoalveolar lavage (BAL) fluid. The current study investigated the vitreous lymphocyte subsets of ocular sarcoidosis to elucidate the immunologic features of this disorder in the eye. Case-control study. Fifty-one eyes of 38 patients with ocular sarcoidosis, confirmed by international diagnostic criteria, were enrolled in this study. Twenty-seven eyes of 26 patients with other causes of uveitis were enrolled as nonsarcoid controls. Evaluation of diagnostic tests for cell profiles of ocular sarcoidosis. Lymphocytes in the vitreous samples were analyzed by cytology, polymerase chain reaction, and flow cytometry. Peripheral blood was also obtained from each patient and analyzed in comparison with the vitreous samples. CD4/CD8 ratios of vitreal and peripheral T lymphocytes. CD4/CD8 ratios of the vitreous T lymphocytes were significantly higher in ocular sarcoidosis than in nonsarcoidosis vitreous samples. In the patients with ocular sarcoidosis, the CD4/CD8 ratios of vitreal T lymphocytes were significantly higher than the CD4/CD8 ratios of peripheral T lymphocytes. No significant differences were found between the CD4/CD8 ratios of vitreal and peripheral T lymphocytes in the patients without sarcoidosis. Moreover, the CD4/CD8 ratios of peripheral T lymphocytes in the patients with ocular sarcoidosis were significantly higher than in patients without sarcoidosis. The sensitivity and specificity of the vitreal CD4/CD8 ratio were 100% and 96.3%, respectively, for the diagnosis of ocular sarcoidosis. Our findings suggest that the CD4/CD8 ratio of vitreous-infiltrating lymphocytes has high diagnostic value in ocular sarcoidosis, comparable to that of the CD4/CD8 ratio in BAL fluid lymphocytosis for pulmonary sarcoidosis. Furthermore, a high CD4/CD8 ratio of peripheral blood T lymphocytes should be one of the laboratory findings for ocular sarcoidosis. Diagnostic vitrectomy using flow cytometric analysis may be a useful adjunct for the diagnosis of ocular sarcoidosis, particularly in complex cases.

Induction of protective immunity against brucellosis in mice by vaccination with a combination of naloxone, alum, and heat-killed Brucella melitensis 16 M

A T-helper cell type 1-specific response leads to the elimination of intracellular infection with Brucella. Studies have shown that naloxone (NLX) can promote a cellular immune response in this respect. The current study was carried out to evaluate the induction of protective immunity in mice against brucellosis by vaccination with a combination of NLX, alum, and heat-killed Brucella melitensis 16 M (HKB). Mice were categorized into five groups and received intraperitoneal vaccination on Days 0 and 7. Then serum levels of interferon (IFN)-γ and interleukin (IL)-4, the bacterial load, and the survival rate were measured 2 weeks after the last vaccination. The serum levels of IFN-γ, IL-4, and immunoglobulin G in the NLX+alum+HKB group were shown to be significantly increased (p<0.05). Furthermore, the lowest bacterial load was observed in this group. The survival rate in groups vaccinated with combinations containing adjuvants was 100%. The combination of NLX and alum enhanced the immunogenicity of HKB, which can be used in the vaccination of animals and humans at risk of the disease.

CD4+LAP+ and CD4+CD25+Foxp3+ Regulatory T Cells Induced by Nasal Oxidized Low-Density Lipoprotein Suppress Effector T Cells Response and Attenuate Atherosclerosis in ApoE−/− Mice

Increasing studies have demonstrated that atherosclerosis is a chronic immunoinflammatory disease, and that oxidized low-density lipoprotein (oxLDL)-specific T cells contribute to the autoimmune process in atherosclerosis. Oral administration of oxLDL, which was identified as a candidate autoantigen in atherosclerosis, was shown to induce tolerance and suppress atherogenesis. However, the precise mechanisms of mucosal tolerance induction, in particular nasal tolerance, remain unknown. In this study, we explored the effect of nasal oxLDL on atherosclerosis as well as the cellular and molecular mechanisms leading to atheroprotective responses, and then found that nasal oxLDL drastically ameliorate the initiation (47.6 %, p < 0.001) and progression (21.1 %, p = 0.001) of atherosclerosis. Most importantly, a significant 35.8 % reduction of the progression of atherosclerosis was observed in the enhanced immunization group (p < 0.001). These effects were accompanied by a significant increase in CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) and CD4(+)CD25(+)Foxp3(+) Tregs in spleens and cervical lymph nodes, together with increased transforming growth factor (TGF)-β production and suppressed T-helper cells type 1, 2, and 17 immune responses. Surprisingly, neutralization of TGF-β in vivo partially counteracted the protective effect of nasal oxLDL treatment, indicating that the presence of TGF-β was indispensable to CD4(+)LAP(+) Tregs and CD4(+)CD25(+)Foxp3(+) Tregs to acquire regulatory properties. Our studies suggest that CD4(+)LAP(+) Tregs and CD4(+)CD25(+)Foxp3(+) Tregs induced by nasal delivery of oxLDL can inhibit oxLDL-specific T cells response and ameliorate atherosclerosis process.

Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation.

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (TH2) cytokine–dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we identify that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum immunoglobulin E (IgE) levels, increased steady–state circulating basophil populations, and exaggerated basophil–mediated TH2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of MyD88 was required to limit serum IgE levels and circulating basophil populations in mice. Commensal–derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal–derived signals influence basophil hematopoiesis and susceptibility to TH2 cytokine–dependent inflammation and allergic disease.

An Integrated RNA-seq Atlas of the Murine T-Helper Cell Transcriptome

T-helper cells play an important role in mediating the immune response, and with the advent of next generation sequencing, significant insights can be gained into the T-helper cell transcriptome. One of the barriers to analyzing next-generation sequencing data, such as that generated by RNA-seq analyses, is that many of the statistical properties concerning quantification (ie. RPKM [1] vs. FPKM [2]), normalization [3], and differential expression (using methods such as edger [4], DESeq [5], and Cuffdiff [6]) of the data are still not clearly understood. Building on previous investigations into the bimodality of transcript expression [7], a computational pipeline was created to integrate various methods of expression quantification, cell type clustering, differential expression analyses, gene annotation methods, and novel transcript identification into a murine T-helper cell expression atlas. By integrating these various analyses, it was possible to identify key signature genes (transcription factors, cytokines, receptors, and other molecules) that distinguish the various T-helper cell types from each other, in addition to novel transcripts. This expression atlas, which is easily accessible as a user-friendly online resource at http://www.thelpercell.com, will form the basis for future investigations into immune regulation and function using network-based analyses. This work is relevant to the goals of SEQAHEAD because it represents a major step forward in the integration and comparison of various methods of expression quantification, differential expression analysis, and annotation of RNA-seq data. The computational principles presented here could potentially be applicable to many other fields of molecular biology and medicine.

JCM-16021, a Chinese Herbal Formula, Attenuated Visceral Hyperalgesia in TNBS-Induced Postinflammatory Irritable Bowel Syndrome through Reducing Colonic EC Cell Hyperplasia and Serotonin Availability in Rats

The present study aimed to investigate the analgesic effect of JCM-16021, a revised traditional Chinese herbal formula, on postinflammatory irritable bowel syndrome (PI-IBS) in rats. The trinitrobenzene sulfonic (TNBS) acid-induced PI-IBS model rats were orally administrated with different doses of JCM-16021 (1.2, 2.4, and 4.8 g/kg/d) for 14 consecutive days. The results showed that JCM-16021 treatment dose-dependently attenuated visceral hyperalgesia in PI-IBS rats. Further, the colonic enterochromaffin (EC) cell number, serotonin (5-HT) content, tryptophan hydroxylase expression, and mechanical-stimuli-induced 5-HT release were significantly ameliorated. Moreover, the decreased levels of mucosal cytokines in PI-IBS, especially the helper T-cell type 1- (Th1-) related cytokine TNF-α, were also elevated after JCM-16021 treatment. These data demonstrate that the analgesic effect of JCM-16021 on TNBS-induced PI-IBS rats may be medicated via reducing colonic EC cell hyperplasia and 5-HT availability.

T-helper cell type 1 memory cells and postoperative ileus in the entire gut

The pathophysiological riddle of the clinically important postoperative ileus (POI) has been solved more and more over the last decade. The POI is caused by inflammation and paralysis at the manipulated site propagating to the entire, unmanipulated gastrointestinal tract. Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how macrophages are activated, particularly those in unmanipulated areas. In addition to direct or neurally mediated activation of intestinal macrophages, a new immunologically mediated activation has been proposed. Recently, it has been shown that the surgical trauma induces interleukin-12 (IL-12) production by intestinal dendritic cells, which activates TH1-memory cells at the manipulated site. Those TH1-memory cells produce interferon-γ (IFN-γ). Those TH1 CCR9 cells also migrate to unmanipulated parts of the gastrointestinal tract. Their IFN-γ stimulates intestinal macrophages to produce nitirc oxide paralyzing myocytes leading to gastrointestinal hypomotility. The involvement of the adaptive (T-helper type 1 cell-mediated immune response) and of the innate (mast cells, intestinal macrophages) immune system in the pathophysiology of POI displays possible targets for objective monitoring and treatment of POI.