bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interleukin-10 inducing effect of transforming growth factor-β on human naive CD4+ T cells from cord blood is restricted to the TH1 subset
Authors: Kapitein B , Tiemessen M M , Liu W M , Van Ieperen-van Dijk A G , Hoekstra M O , Van Hoffen E , Knol E F 
Published: August 2010

SummaryTransforming growth factor (TGF-β) seems to play a role in the regulation of immune responses, mainly by its suppressive function towards cells of the immune system. However, both in mice and human, conflicting data are published on the capacity of TGF-β to induce interleukin (IL)-10 secretion in both naive and skewed T cell populations. Our aim was to test the IL-10-inducing capacity of TGF-β in both naive and skewed cord blood mononuclear cells (CBMCs) and elucidate the mechanism by which TGF-β exerts its effect. Therefore, naive CBMCs and CBMCs during skewing under T helper 1 (Th1) and Th2 polarizing conditions were stimulated with CD3 and/or CD28 in the presence or absence of TGF-β. Proliferation, cytokine production and mRNA expression of transcription factors was measured. TGF-β enhanced the IL-10 production in Th1 and naive cells only, and suppressed the TH1 phenotype as demonstrated in cytokine levels and T-box expression in T cells (T-bet) expression. Interestingly, forkhead box p3 (Foxp3) expression tended to increase in both Th1 and Th2 cells. These data indicate that TGF-β can induce a regulatory phenotype in both naive and Th1-polarized cells derived from cord blood. The induction of IL-10 was not observed in Th2-polarized phenotype, indicating that TGF-β might be especially of interest for immunomodulation in Th1 cells.
Immunological responses and protective immunity against tuberculosis conferred by vaccination of Balb/C mice with the attenuated Mycobacterium tuberculosis (phoP) SO2 strain
Authors: Aguilar D , Infante E , Martin C , Gormley E , Gicquel B , Hernandez Pando R 
Published: August 2010

Summary
The Mycobacterium tuberculosis phoP mutant strain SO2 has been shown previously to be more attenuated than Mycobacterium bovis bacillus Calmette–Guérin (BCG) and confers protective immunity against tuberculosis in mice and guinea pig models. In this study we have investigated the survival and immunological responses of Balb/c mice infected with the M. tuberculosis SO2 strain. All Balb/C mice survived intratracheal infection with M. tuberculosis SO2 strain under conditions where all the mice infected with the parental M. tuberculosis MT103 had died after 9 weeks. Infection of Balb/c mice with M. tuberculosis SO2 was associated with comparatively lower levels of interferon (IFN)-γ, interleukin (IL)-4 and tumour necrosis factor (TNF)-α and higher levels of inducible nitric oxide synthase (iNOS) during the late stage of infection, when compared with M. tuberculosis MT103 infection. The delayed-type hypersensitivity (DTH) response against M. tuberculosis culture filtrates was similar in mice infected with either the M. tuberculosis phoP SO2 strain or M. tuberculosis MT103. The protective efficacy of M. tuberculosis SO2 was compared with M. bovis BCG when delivered subcutaneously to groups of Balb/C mice. Following intratracheal challenge with M. tuberculosis H37Rv, protection was generated by 60 days post-challenge in mice vaccinated with either vaccine. At day 120 post-challenge the levels of protection were still significantly greater when compared with the non-vaccinated control group. The levels of protection conferred by vaccination with M. tuberculosis SO2 or with M. bovis BCG were similar, as measured by granuloma coalescence and pneumonia in addition to growth reduction of M. tuberculosis H37Rv.
Vitamin E down-modulates mitogen-activated protein kinases, nuclear factor-κB and inflammatory responses in lung epithelial cells
Authors: Ekstrand-Hammarström B , Österlund C , Lilliehöök B , Bucht A 
Published: August 2010

Summary
The airway epithelium plays an active role in acute lung inflammation by producing chemotactic factors and by expressing cell adhesion molecules involved in the migration of leucocytes to extravascular spaces. We have reported previously that neutrophil migration to airways can be down-modulated by exogenously administered vitamin E (α-tocopherol). The mechanism for this effect is not well understood, however. The action of α-tocopherol was investigated in human alveolar type II and bronchial epithelial cells stimulated with tumour necrosis factor-α. Treatment of alveolar epithelial cells with α-tocopherol resulted in down-regulated cell surface expression of intercellular adhesion molecule-1 (ICAM-1). On bronchial epithelial cells, both ICAM-1 and vascular adhesion molecule-1 were decreased, leading to diminished adherence of leucocytes to the cells. The production of the neutrophil chemoattractant interleukin-8 was attenuated in both alveolar and bronchial cells. These effects were preceded by reduced activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase (ERK1/2) and p38, as well as down-regulation of nuclear factor-κB. Comparing the effects of α-tocopherol with that of specific inhibitors of MAPK and protein kinase C (PKC) revealed that effects appear to be partly independent of PKC inhibition. These results implicate the anti-inflammatory action of α-tocopherol in addition to its anti-oxidant properties.
Loss of expression of antigen-presenting molecules in human pancreatic cancer and pancreatic cancer cell lines
Authors: Pandha H , Rigg A , John J , Lemoine N 
Published: August 2010

SummaryTumours evade immune recognition and destruction through loss or down-regulation of expression of antigen processing and antigen-presenting molecules such as the human leucocyte antigen (HLA class I) and transporter for antigen presentation (TAP). This study examined the expression of HLA class I, class II and TAP in human pancreatic carcinoma tissue and 19 immortalized pancreatic cancer lines using a panel of antibodies directed against allele-specific as well as monomorphic determinants of these molecules. In tissue samples, reduction or loss of HLA class I and TAP was observed in 76% of cases, loss or down-regulation of TAP expression in 53%. In pancreatic cell lines down-regulation or loss of class I and TAP expression was also observed frequently. However, reductions in class I and TAP expression were reversible upon exposure to interferon-γin vitro, suggesting a regulatory rather than structural defect in these genes. De novo class II expression was observed in 26% of tumours and 42% of cell lines and may reflect the differentiation status of the cells. The high rate of class I and TAP loss has implications for immunotherapy strategies for pancreatic cancer, as such changes could facilitate a selective growth advantage for malignant cells. However, the reinduction of expression of these molecules with cytokines such as interferon-γ may ultimately allow their cytotoxic T cell-mediated destruction.
Translational Mini-Review Series on Toll-like Receptors:&#x2028;Toll-like receptor ligands as novel pharmaceuticals for allergic disorders
Authors: Goldman M 
Published: August 2010

SummaryCharacterization of the Toll-like receptor (TLR) family and associated signalling pathways provides a key molecular basis for our understanding of the relationship between exposure to microbial products and susceptibility to immune-mediated disorders. Indeed, ligation of TLR controls innate and adaptive immune responses by inducing synthesis of pro- as well as anti-inflammatory cytokines and activation of effector as well as regulatory lymphocytes. TLRs are therefore considered as major targets for the development of vaccine adjuvants, but also of new immunotherapies. Herein, we review the potential of TLR ligands as a novel class of pharmaceuticals for the prevention or treatment of allergic disorders.
Translational Mini-Review Series on Toll-like Receptors:&#x2028;Recent advances in understanding the role of Toll-like receptors in anti-viral immunity
Authors: Bowie A G 
Published: August 2010

Summary
Toll-like receptors (TLRs) respond to pathogens to initiate the innate immune response and direct adaptive immunity, and evidence to date suggests that they have a role in the detection of viruses. Many viral macromolecules have been shown to activate anti-viral signalling pathways via TLRs, leading to the induction of cytokines and interferons, while viruses also have means of not only evading detection by TLRs, but also of subverting these receptors for their own purposes. This review discusses the role of TLRs in the context of other known viral detection systems, and examines some of the often surprising results from studies using mice deficient in TLRs and their adaptors, in an attempt to unravel the particular contribution of TLRs to anti-viral immunity.
Human ovarian tumour-derived chaperone-rich cell lysate (CRCL) elicits T cell responsesin vitro
Authors: Li G , Zeng Y , Chen X , Larmonier N , Sepassi M , Graner M W , Andreansky S , Brewer M A , Katsanis E 
Published: August 2010

SummaryTumour-derived chaperone-rich cell lysate (CRCL), which is made up of numerous heat shock proteins, has been used successfully to generate tumour-specific T cell responses and protective immunity against a wide range of murine tumours. In this study, we have investigated the potency of human ovarian cancer-derived CRCL to activate dendritic cells (DC) and to generate tumour-specific T cells in vitro. CRCL was generated from primary ovarian cancers and SKOV3-A2, a HER2/neu, Wilm's tumour gene 1 (WT1) and human leucocyte antigen (HLA)-A2 positive human ovarian tumour cell line. Peripheral blood mononuclear cells from both HLA-A2+ healthy donors and HLA-A2+ ovarian cancer patients were stimulated weekly with autologous DC loaded with ovarian tumour-derived CRCL. After four to six stimulations in vitro, specific cytokine secretion and cytotoxicity were measured. CRCL promoted interleukin (IL)-12 secretion and enhanced the immunostimulatory capacity of DC. T cells from healthy controls and from ovarian cancer patients secreted higher amounts of interferon-γ following in vitro restimulation with ovarian cancer-derived CRCL than with HER2/neu or WT1 peptide-pulsed DC. We were also able to generate cytotoxic T lymphocyte activity against cancer-specific antigens such as HER2/neu and WT1 from all healthy donors, but from only one of the four ovarian cancer patients with bulky disease. These preliminary results substantiate further the concept that CRCL may prove to be a potent adjuvant for women suffering from ovarian cancer and that this personalized vaccine may be a promising approach for active immunotherapy.
Interleukin-6 expression and gene polymorphism are associated with severity of periodontal disease in a sample of Brazilian individuals
Authors: Moreira P R , Lima P M A , Sathler K O B , Imanishi S A W , Costa J E , Gomez R S , Gollob K J , Dutra W O 
Published: August 2010

Summary
Interleukin (IL)-6 is an inflammatory mediator involved in bone resorption. G/C polymorphism at position −174 of the IL-6 gene has been reported to influence IL-6 expression, with the G allele associated with higher expression levels. The aims of this study were to investigate the expression of IL-6 as well as the incidence of IL-6 (−174) gene polymorphism and their correlation to the severity of periodontitis in Brazilians. Peripheral blood mononuclear cells were collected from 12 non-smoker individuals with periodontitis for evaluation of IL-6 expression using flow cytometry. We observed a positive correlation between the mean clinical attachment loss and intensity of expression of IL-6, in which the greater the attachment loss, the higher the expression of IL-6 (P = 0·007, R2 = 0·52). Also, patients with severe periodontitis displayed a higher intensity of IL-6 expression compared to moderate periodontitis (P = 0·04). To determine the occurrence of IL-6 gene polymorphism, DNA was obtained from oral swabs of 209 Brazilian individuals with and without periodontitis. Polymerase chain reaction, restriction endonuclease digestion and electrophoresis were performed, allowing for detection of the IL-6 (−174) polymorphism. We observed that non-smokers with moderate periodontitis (P = 0·05) and control (P = 0·04) groups displayed a higher incidence of the G– genotype when compared to severe periodontitis. This suggests that the G– genotype may represent a protective role in severity of periodontitis. Thus, the increased expression of IL-6 and IL-6 (−174) polymorphism are associated with periodontal disease severity in Brazilian individuals.
Translational Mini-Review Series on Type 1 Diabetes: Immune-based therapeutic approaches for type 1 diabetes
Authors: Staeva-Vieira T , Peakman M , Von Herrath M 
Published: August 2010

SummaryType 1 diabetes (T1D) is often considered the prototype organ-specific autoimmune disease in clinical immunology circles. The key disease features − precise destruction of a single endocrine cell type occurring on a distinct genetic and autoimmune background − have been unravelled in recent years to such an extent that there is a growing expectation that the disease should be curable. T1D is something of an orphan disease, currently managed by endocrinologists yet dependent upon the wit of immunologists, both basic and clinical, to find the best approaches to prevention and cure. Type 1 diabetes thus represents one of the most active arenas for translational research, as novel immune-based interventions find their way to the clinic. The first serious attempt at immune-based treatment for T1D was in 1984, the first at prevention in 1993; current and planned trials will take us into the next decade before reporting their results. This paper represents the first attempt at a comprehensive review of this quarter century of endeavour, documenting all the strategies that have emerged into clinical studies. Importantly, the intense clinical activity has established robust infrastructures for future T1D trials and frameworks for their design. The evident success of the monoclonal anti-CD3 antibody trials in established T1D demonstrate that modulation of islet autoimmunity in humans after the onset of overt disease can be achieved, and give some reason to be cautiously optimistic for the ability of these and other agents, alone and in combination, to provide an effective immunotherapy for the disease.
The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma
Authors: Lee J-H , Yu H-H , Wang L-C , Yang Y-H , Lin Y-T , Chiang B-L 
Published: August 2010

SummaryOur purpose was to determine whether numbers of CD4+CD25+ T [T regulatory (Treg)] cells and mRNA expression of functional molecules of Treg are related to airway allergy and disease severity in 51 paediatric patients with allergic rhinitis or bronchial asthma and 47 healthy controls. Surface markers were evaluated with flow cytometry, and mRNA was determined with real-time polymerase chain reaction. Children with allergic disease had fewer CD4+CD25+ T cells (8·49% ± 2·41% versus 9·58% ± 2·43%, P &lt; 0·05) and CD4+CD25hi T cells (1·32% ± 0·68% versus 1·70% ± 0·68%, P &lt; 0·01) than control subjects. Numbers of CD4+CD25+ and CD4+CD25hi T lymphocytes were higher in children with persistent allergic rhinitis and/or moderate–severe bronchial asthma than in those with respective milder disease. The number of Treg cells was correlated positively with total immunoglobulin E level. The mRNA expression of forkhead box P3 (FoxP3) was increased in moderate–severe versus mild asthma (2·93 ± 0·38 versus 1·60 ± 0·31, P &lt; 0·01). Patients with moderate–severe bronchial asthma also had increased mRNA expression of interleukin (IL)-10 compared with patients with mild asthma (15·24 ± 4·07 versus 3·77 ± 2·18, P &lt; 0·01). The suppressive function of Treg cells from patients with more severe asthma was competent in vitro. On average, decreased numbers of Treg cells in children with allergic airway disease might represent a defect of the Treg population. With increased expression of FoxP3 and IL-10 in Treg from patients with relatively severe allergic disease, adaptive and functional Treg might be generated in response to aggravated atopy and disease severity.
Toll-like receptor 4-dependent recognition of structurally different forms of chemically synthesized lipid As ofPorphyromonas gingivalis
Authors: Sawada N , Ogawa T , Asai Y , Makimura Y , Sugiyama A 
Published: August 2010

SummaryPorphyromonas gingivalis is a Gram-negative anaerobic oral black-pigmented bacterium closely associated with chronic periodontitis. Lipopolysaccharide (LPS) derived from P. gingivalis is shown to be unusual because the LPS contains a greater number of lipid A species, such as tri-, tetra-, and/or penta-acylated lipid As. In this study, a lipid A possessing penta-fatty acyl chains derived from P. gingivalis strain 381 (compound PG-381–5FA) was synthesized, and examined for its immunobiological activities, compared with a tri-acylated lipid A (compound PG-381–3FA) synthesized previously. Compound PG-381-5FA, similar to compound PG-381-3FA, demonstrated weaker activity in a Limulus test as compared with Escherichia coli-type synthetic lipid A (compound 506). Compound PG-381-5FA, followed by compound PG-381-3FA, induced KC, interleukin-6, and tumour necrosis factor-α production in peritoneal macrophages from LPS-responsive C3H/HeN mice, but not in those from LPS-hyporesponsive C3H/HeJ mice. Furthermore, compound PG-381-5FA, as well as compound PG-381-3FA, activated nuclear factor-κB via Toll-like receptor (TLR)4/mD-2, but not TLR2, in a manner similar to compound 506, and worked as an antagonist for compound 506-induced cell activation. In the case of human peripheral blood mononuclear cells, compound PG-381-5FA showed much stronger IL-6-inducing activity than compound PG-381-3FA. The present results demonstrate that the chemical synthesis of a penta-acylated lipid A, mimicking the natural lipid A portion of LPS from P. gingivalis, is attributable to immune cell activation through TLR4, similar to that of compound 506.
Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation
Authors: Clausen J , Wolf D , Petzer A L , Gunsilius E , Schumacher P , Kircher B , Gastl G , Nachbaur D 
Published: August 2010

Summary
To define the role of quantitative graft composition and donor killer-cell immunoglobulin-like receptor (KIR) genotype in clinical outcome following unmanipulated peripheral blood stem cell transplantation (PBSCT) from human leucocyte antigen (HLA)-identical siblings, 43 consecutive transplants for haematological malignancies were analysed retrospectively. Twenty-four patients underwent myeloablative conditioning and 19 received busulphan/fludarabine-based reduced intensity conditioning (RIC). In patients with acute myelogenous leukaemia or myelodysplastic syndrome (AML/MDS; n = 18), no relapse occurred following transplants meeting both a high (above median) natural killer (NK) cell count and missing HLA-ligand(s) to donor's KIR(s), compared to all other AML/MDS patients (0% versus 44%; P = 0·049). Missing HLA-B and/or HLA-C ligand combined with missing HLA-A3/11 (KIR3DL2 unblocked) predicted for reduced relapse incidence regardless of diagnosis or conditioning type (P = 0·028). Moreover, in AML/MDS patients, this constellation predicted superior overall survival (OS) (P = 0·046). Transplants with more than two different activating donor KIRs were associated with an increased risk for non-relapse mortality (NRM), both by univariate and multivariate analysis. Quantitative graft composition had a significant impact exclusively in RIC transplants. Here, a trend towards reduced relapse incidence was found in patients receiving high numbers of NK cells (16% versus 54%; P = 0·09). In patients receiving high versus low T cell numbers, OS was superior (83% versus 37%; P = 0·01), due mainly to reduced NRM (0% versus 33%; P = 0·046). By multivariate analysis, relapse risk was decreased significantly in patients receiving high NK cell numbers (P = 0·039). These data suggest that both the number of transplanted NK cells and the donor KIR genotype play a role in graft-versus-malignancy mechanisms in HLA-identical PBSCT.
Glucocorticoid-induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis
Authors: Bae E , Kim W-J , Kang Y-M , Suk K , Koh E-M , Cha H-S , Ahn K-S , Huh T-L , Lee W-H 
Published: August 2010

Summary
Glucocorticoid-induced tumour necrosis factor receptor (TNFR)-related protein (GITR) is one of the T cell co-stimulatory molecules and is associated with the pathogenesis of a number of autoimmune diseases. We investigated the expression patterns of GITR in human arthritic synovium and the role of GITR in the pathogenesis of rheumatoid arthritis (RA). Immunohistochemical analyses revealed the expression of GITR and its cognate ligand, GITRL, in macrophages in RA, but not in osteoarthritis (OA), synovium. To investigate the role of GITR in macrophage functions, primary macrophages from RA patients and a human macrophage cell line, THP-1, were analysed. Stimulation of the macrophages with anti-GITR monoclonal antibody induced up-regulation of intercellular adhesion molecule (ICAM)-1 and subsequent aggregation/adhesion, which was enhanced by the presence of extracellular matrix proteins and blocked by anti-ICAM-1 monoclonal antibody. The validity of these in vitro observations was confirmed by immunohistochemical analyses of RA synovium, which showed strong expression of ICAM-1 in GITR-positive macrophages. Additionally, GITR stimulation induced expression of proinflammatory cytokines/chemokines and matrix metalloproteinase-9 in synovial macrophages. These data indicate that GITR, expressed on macrophages in human RA synovium, may enhance inflammatory activation of macrophages by promoting cytokine gene expression and adhesion between cells and to extracellular matrix in RA synovium.
Freshly isolated Vα24+ CD4+ invariant natural killer T cells activated by α-galactosylceramide-pulsed B cells promote both IgG and IgE production
Authors: Rossignol A , Barra A , Herbelin A , Preud'homme J-L , Gombert J-M 
Published: August 2010

SummaryCD1d-restricted invariant natural killer T (iNK T) cells activated by their experimental ligand α-galactosylceramide (α-GC) can produce both T helper 1 (Th1) and Th2 cytokines and display regulatory functions. Recent studies identified CD4+ and CD4– CD8– double-negative (DN) iNK T cells as the two major components of the human population and suggest that they display a Th2 and a Th1 profile, respectively. We compared the Th2-promoting activity of freshly isolated human CD4+ and DN iNK T cells in terms of their capacity to induce Ig production by autologous B cells. Secretion of IgG and IgE but not IgM was enhanced by the CD4+ T cell subset (including iNK T cells) but not by its DN counterpart. iNK T cells were directly responsible for this pro-Th2 effect, as demonstrated by the requirement for both α-GC stimulation and CD1d presentation, as well as by its disappearance upon iNK T cell depletion. Interaction with iNK T cells led to progressive accumulation of isotype-switched and activated B cells. Myeloid dendritic cells (DC) completely block the induction of Ig production in co-culture. This dominant inhibitory effect of myeloid DC was concomitant with a specific loss of interleukin (IL)-4 production by CD4+ iNK T but not by conventional T cells. These data support the conclusion that, conversely to the interferon (IFN)-γ-producing DN human iNK T cell population, interleukin (IL)-4-producing CD4+ iNK T cells can activate and help B cells to produce both IgG and IgE through a CD1d-dependent mechanism, in keeping with a functional Th1/Th2 dichotomy between these subsets.