bluuebunny/crossref_metadata_2025 huggingface dataset:
Origin of CD57+ T cells which increase at tumour sites in patients with colorectal cancer
Authors: Okada T , Hai T , Awach1 Y K , Moroda T , Takii Y , Hatakeyama K , Abo T
Published: July 2010

Human T cells carrying natural killer (NK) markers, CD57 or CD56 antigens, appear to be distinguishable from other T cell subsets in terms of their granular lymphocyte morphology and their numerical increase in patients with AIDS and in recipients of bone marrow transplantation. At the begining of this study, we observed that CD57+ T cells as well as CD56+ T cells were abundant at tumour sites in many patients with colorectal cancer. Since all these findings for CD57+ T cells are quite similar to those of extrathymic T cells seen in mice, we investigated how CD57+ T cells are distributed to various immune organs in humans. They were found to be present mainly in the bone marrow and liver, but to be completely absent in the thymus. Similar to the case of extrathymic T cells in mice, they were observed to consist of double-negative CD48+ subsets as well as single-positive subsets (preponderance of CD8+ cells), and to contain a considerable proportion of γδ T cells. These features are striking when compared with those of CD57+ T cells, which are characterized by an abundance of CD4+ subsets and αβ T cells. Not only at tumour sites but also in the peripheral blood, some patients with colorectal cancer displayed elevated levels of CD57+ cells. These results suggest that CD57+ T cells may be of extrathymic origin, possibly originating in the bone marrow and liver, and may be associated with tumour immunity, similar to another extrathymic population of CD56+ T cells in humans.
Localization of T cell receptor (TCR)- γδ+ T cells into human colorectal cancer: flow cytometric analysis of TCR-γδ expression in tumour-infiltrating lymphocytes
Authors: Watanabe N , Hizuta A , Tanaka N , Orita K
Published: July 2010

We analysed TCR-γδ expression in tumour-infiltrating lymphocytes (TIL) obtained from 13 patients with colorectal cancer and simultaneously isolated the T lymphocytes from normal intestinal tissue (IL) to compare the frequencies of TCR-γδ expression in TIL, IL. and peripheral blood lymphocytes (PBL) in the same patient. Flow cytometric analysis showed that the frequency of TCR-γδ expression in TIL (275 ± 1·84%) was significantly lower than that in IL (15·28 ± 9·45%, P < 001). However, a larger quantity of TIL was separated than IL per unit weight of specimen, so the total number of γδ T cells obtained per unit weight was not different between tumour tissue and normal intestine. In addition, phenotypic analysis revealed that about half of the TCR-γδ TIL were CD8+ (CD4+, 3·0 ± 3·1%; CD8+, 54·7 ± 19·9%, mean ± s.d. of five patients), and a very similar result was obtained in TCR-γδ+ IL (CD4+ 2·7 ± 2·4%; CD8+, 53·1 ± 17·4%). In contrast, most TCR-γδ+ PBL were double-negative (CD4+. 3·2 ± 3·0%; CD8+ 20·6 ±7·4%). These results indicated that TCR-γδ+ CD8+ T cells selectively and consistently localized in colorectal tumour tissue, similarly to normal intestinal epithelium.
The effect on immunity of long-term intensive training in elite swimmers
Authors: Gleeson M , Mcdonald W A , Cripps A W , Pyne D B , Clancy R L , Fricker P A
Published: July 2010

The impact of long-term training on systemic and mucosal immunity was assessed prospectively in a cohort of elite swimmers over a 7-month training season in preparation for national championships. The results indicated significant suppression (P < 0.05) of serum IgA. IgG and IgM and salivary IgA concentration in athletes associated with long-term training at an intensive level. There was also a trend towards lower IgG2 subclass levels in serum in athletes compared with controls (P= 0.07). There were no significant changes in numbers or percentages of B or T cell subsets, but there was a significant fall in natural killer (NK) cell numbers and percentages in athletes over the training season (P < 0.05). After individual training sessions there was a significant decrease in salivary IgA levels for athletes compared with controls (P= 0.02). In athletes there was a downward trend in salivary IgA levels over the 7-month training period in both the pre-exercise (P= 0.06) and post-exercise samples (P= 0.04). There were no significant trends in salivary IgG levels over the study period in either athletes or controls. The only significant change in salivary IgM levels was an increase in detection rate in the pre-competition phase in athletes (P= 0.03). The study suggests that training of elite athletes at an intensive level over both short- and long-time frames suppresses both systemic and mucosal immunity. Protracted immune suppression linked with prolonged training may determine susceptibility to infection, particularly at times of major competitions.
T cells stimulatedin vitrohave a suppressive function but do not contain only regulatory T cells
Authors: Valencic E , Piscianz E , Tommasini A , Granzotto M
Published: July 2010

The generation of regulatory T cells (Tregs) in vitro represents an attractive possibility to set up cellular therapies that could prevent and cure autoimmune disorders. Different methods have been proposed to generate Tregs  in vitro and to evaluate their phenotype and function. Moreover, the overlap between generation of activated and regulatory cells could often be underestimated. We showed that in vitro treatment of CD4+ CD25– lymphocytes with different stimuli leads to a good expression of CD25 and forkhead box P3 (FoxP3) on most cells, but to a full Treg phenotype (including CD127 negativity) in only a minor percentage of cells, ranging from 17·38% of cells treated with phytohaemagglutinin (PHA) to 50·91% of cells treated with T cell receptor (TCR) stimulation in association with transforming growth factor (TGF)-β. Some suppressive activity was demonstrated for T cells activated with all the different stimuli. However, while suppression mediated by TCR/TGF-β treated T cells was associated with an inhibition of both interleukin (IL)-2 and interferon (IFN)-γ in the co-culture supernatant, the suppression observed for PHA-activated cells occurred in the presence of large amounts of these cytokines. In conclusion, also taking into account other recent publications, caution should be taken in interpretation of data in the field of regulatory T cells.
A role for T cell-derived interleukin 22 in psoriatic skin inflammation
Authors: Boniface K , Guignouard E , Pedretti N , Garcia M , Delwail A , Bernard F-X , Nau F , Guillet G , Dagregorio G , Yssel H , Lecron J-C , Morel F
Published: July 2010

Interleukin (IL)-22 is a T cell-derived cytokine that has been reported recently to induce cutaneous inflammation in an experimental murine model of psoriasis, and to induce in vitro an inflammatory-like phenotype. In the present study, we assessed the presence of IL-22 and the IL-22 receptor 1 (IL-22R1) in skin lesions, skin-derived T cells, as well as IL-22 levels in sera from patients with psoriasis. IL-22R1 and IL-10R2 transcripts are expressed at a similar level in psoriatic and healthy skin. In contrast, IL-22 mRNA expression was up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL-22 levels were significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produced higher levels of IL-22 in comparison to peripheral T cells isolated from the same patients. IL-10 was expressed at similar levels in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we show here that supernatants of lesional psoriatic skin-infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions. Taken together, the results reported in this study indicate that IL-22 is a cytokine produced by skin-infiltrating lymphocytes that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.
Increase of CD4+CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+CD25+ T lymphocytes
Authors: Audia S , Nicolas A , Cathelin D , Larmonier N , Ferrand C , Foucher P , Fanton A , Bergoin E , Maynadie M , Arnould L , Bateman A , Lorcerie B , Solary E , Chauffert B , Bonnotte B
Published: July 2010

We determined the number and functional status of CD4+CD25high regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide. Treg numbers were significantly higher in 49 patients with metastatic cancer (9·2% of CD4+ T cells) compared to 24 healthy donors (7·1%). These cells expressed the transcription factor forkhead box P3 (FoxP3), glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) and intracellular CD152, and demonstrated a suppressive activity in vitro against CD4+CD25– autologous proliferation. At a single intravenous infusion, cyclophosphamide failed, in association with a non-specific immunotherapy by intratumoral bacille Calmette–Guérin (BCG), to modulate significantly Treg numbers or function. Metastatic cancer is associated with an expansion of peripheral blood CD4+CD25highFoxP3+GITR+CD152+Treg cells whose immunosuppressive properties do not differ from those of healthy subjects. Moreover, cyclophosphamide administration may not represent an optimal therapy to eliminate Treg, which further underlines the need to identify specific agents that would selectively deplete these cells.
Shift of C3 deposition from localization in the glomerulus into the tubulo-interstitial compartment in the absence of secreted IgM in immune complex glomerulonephritis
Authors: Vaculik C , Rüger B M , Yanagida G , Hollemann D , Soleiman A , Losert U M , Chen J , Fischer M B
Published: July 2010

The role of secretory IgM in protecting kidney tissue from immune complex glomerulonephritis induced by 4 mg horse spleen apoferritin and 0·05 mg lipopolysaccharide has been investigated in mutant mice in which B cells do not secrete IgM, but are capable of expressing surface IgM and IgD and secreting other Ig isotypes. Glomerular size, number of glomeruli per cross-section, glomerular cellularity and urine content of protein and creatinine was comparable in treated secreted IgM (sIgM)-deficient and wild-type mice. Assessment of urinary proteins by sodium dodecyl sulphate-polyacrylamide gel electrophoresis showed a 30 kDa low molecular weight protein in treated sIgM-deficient animals only, reflecting dysfunction of proximal tubules. A shift of bound C3 from glomeruli to the tubulo-interstitial compartment in sIgM-deficient mice also suggests tubulo-interstitial damage. In contrast, local C3 synthesis within the kidney tissue did not differ between the two treated groups. Apoptosis physiologically present to maintain kidney cell homeostasis was increased slightly in treated wild-type mice. These results indicate that secretory IgM can protect the tubulo-interstitial compartment from immune complex-induced damage without having an effect on the glomerulus.
Comparative therapeutic effects of orally administered 1,25-dihydroxyvitamin D3 and 1alpha-hydroxyvitamin D3 on type-1 diabetes in non-obese diabetic mice fed a normal-calcaemic diet
Authors: Driver J P , Foreman O , Mathieu C , Van Etten E , Serreze D V
Published: July 2010

Frequent injections of the hormonal form of vitamin D3, 1,25 dihydroxyvitamin D3 (1,25D3) reportedly inhibits autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by correcting some of the abnormalities in antigen-presenting cells which contribute the development of pathogenic T cell responses. This route of administration greatly elevates the levels of these compounds in the bloodstream for hours after treatment, which requires mice to be fed diets formulated to contain much reduced levels of Ca to avoid the toxic effects of hypercalcaemia. In the current work, we demonstrate that feeding 1,25D3 or its synthetic precursor, 1alpha(OH) vitamin D3 (1alphaD3), as part of a T1D supportive chow diet containing normal levels of Ca, is an effective means of reducing the incidence of disease in NOD mice, but the doses required for protection elicited hypercalcaemia. However, T1D protection elicited by D3 analogue feeding appears, at least partially, to have an immunological basis, as splenic T cells from treated mice had a decreased capacity to adoptively transfer disease. Protection is associated with an increased proportion of T cells with CD4+ forkhead box P3+ regulatory phenotype within the islet infiltrate of treated animals. The 1alphaD3 precursor is converted rapidly to the active 1,25D3 isoform in vivo. However, feeding the 1alphaD3 analogue elicited stronger T1D protection than the 1,25D3 compound, but also induced more severe hypercalcaemia. In future, the dietary supplementation of novel low-calcaemic D3 analogues may enable their continuous delivery at levels that inhibit T1D development in susceptible humans consuming normal levels of Ca.
l-Ficolin binding and lectin pathway activation by acetylated low-density lipoprotein
Authors: Faro J , Chen Y , Jhaveri P , Oza P , Spear G T , Lint T F , Gewurz H
Published: July 2010

l-Ficolin, like mannan-binding lectin (MBL), is a lectin pathway activator present in normal human plasma. Upon binding ligand, l-ficolin similarly initiates C4 cleavage via the serine protease MBL-associated serine protease-2 (MASP-2). We sought further insight into l-ficolin binding reactions and MASP-2 activation by passing plasma through GlcNAc-derivatized Sepharose. l-Ficolin bound in 1·0 M NaCl-ethylenediamine tetraacetic acid (EDTA), and remained bound in NaCl-free EDTA, while MASP-2 eluted in proenzyme form (∼20% yield, > 40 000-fold purification). l-Ficolin was eluted with GlcNAc in 1·0 M NaCl (∼10% yield, > 3000-fold purification), with trace amounts of C3, α2-macroglobulin and both native and activated MASP-2. These preparations were utilized to investigate l-ficolin reactivities with acetylated low-density lipoprotein (A-LDL) as a model ligand in albumin-free systems. l-Ficolin bound strongly to A-LDL in the absence as well as presence of calcium, including saline-EDTA, and was optimal in 1·0 M NaCl-EDTA, but binding failed to occur in EDTA in the absence of NaCl. The addition of l-ficolin to immobilized A-LDL resulted in activation of MASP-2 in unmodified but not ficolin-depleted plasma unless l-ficolin was restored. We conclude that A-LDL is a useful ligand for investigation of l-ficolin function; both binding and activation are optimally examined in systems free of albumin; and ligand binding in 1·0 M NaCl in EDTA can be useful in the isolation of l-ficolin and native MASP-2.
Preparing for first-in-man studies: the challenges for translational immunology post-TGN1412
Authors: Dayan C M , Wraith D C
Published: July 2010

Current immunology research is generating many new approaches to immunotherapy. However, the recent disaster surrounding the testing of TGN1412, has unsettled regulators and the pharmaceutical industry regarding new immunotherapies and highlighted the complexities of conducting clinical trials with agents that target the immune system. Here we discuss the critical role for immunologists in ensuring that the development of new immunotherapies continues.
Basal lymphoid aggregates in ulcerative colitis colon: a site for regulatory T cell action
Authors: Sitohy B , Hammarström S , Danielsson Å , Hammarström M-L
Published: July 2010

Regulatory T cells seem to play a central role in maintaining immune tolerance in the gut mucosa. Previously we have shown that interleukin (IL)-10 is produced at high levels in the inflamed colonic tissue of ulcerative colitis (UC) patients. The cellular source was CD4+ T cells, suggesting local activation of regulatory T cells. The present study was performed to determine whether the frequency of regulatory T cells is increased in UC colon and whether they are present in the basal lymphoid aggregates, the prominent microanatomical structure in UC colon. Colonic tissue specimens from UC and control patients were analysed for frequencies of lamina propria lymphocytes expressing the regulatory T cell markers forkhead box protein 3 (FoxP3), CD25 and glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR) as well as CD28, CD4 and CD3 by using marker specific reagents in immunomorphometry. Two-colour immunohistochemistry was used for detection of CD25/IL-10, FoxP3/IL-10 and CD25/FoxP3 double-positive cells. GITR+ and FoxP3+ cells were present in normal colon mucosa, although at a relatively low frequency, and were located preferentially within the solitary follicles. UC was associated with significantly increased frequencies of CD25+, GITR+ and FoxP3+ lamina propria lymphocytes both within the basal lymphoid aggregates and in the lamina propria outside. Many of the CD25+ cells co-expressed FoxP3 as well as IL-10, suggesting that these are indeed IL-10 secreting regulatory T cells, activated in an attempt to counteract the inflammation. Increased frequency of regulatory T cell subtypes seems insufficient to control the disease activity in UC.
T cell activation profiles in Kawasaki syndrome
Authors: Brogan P A , Shah V , Clarke L A , Dillon M J , Klein N
Published: July 2010

Superantigens (SAgs) are potent stimulators of T cells bearing specific Vβ T cell receptors (TCR) and may play a role in the pathogenesis of Kawasaki syndrome (KS), although despite 15 years of intense study this area remains controversial. Because SAgs can cause Vβ restricted T cell activation in the absence of Vβ skewing the aims of this study were to describe a flow cytometric protocol to study both CD4 and CD8 Vβ repertoires, and CD69 expression across the CD4 and CD8 Vβ repertoire in children with KS. Sixteen children with KS were studied. There was no significant increase in overall peripheral blood CD4 or CD8 T cell activation as determined by CD69 expression. However, Vβ restricted CD4 and/or CD8 activation was observed in eight of 11 (72%) of the KS patients, a finding not observed in healthy controls. Thirteen of 16 (81%) of the KS patients had evidence of either Vβ skewing (particularly CD4 Vβ2 and Vβ5·1) and/or Vβ restricted activation. Three patients had Vβ restricted activation in the absence of skewing. We suggest that these preliminary observations highlight the many layers of complexity when considering T cell activation in KS, which could explain some of the conflicting studies regarding peripheral blood T cell activation and Vβ skewing. It is likely that in order to move forward with this debate a combination of detailed microbiological, immunological and molecular techniques applied to individual patients will be required ultimately to prove or refute the SAg hypothesis of KS.
Neurotrophins modulate monocyte chemotaxis without affecting macrophage function
Authors: Samah B , Porcheray F , Gras G
Published: July 2010

Neurotrophins nerve growth factor (NGF), brain-derived growth factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) and their high-affinity tyrosine protein kinase receptor (Trk) family, TrkA, TrkB, TrkC, and low-affinity p75NTR receptor, are key molecules implicated in the development of the central nervous system. Increasing evidence suggests that they also have physiological and pathological roles outside the nervous system. In this study we examined the expression of neurotrophins and their receptors in human activated macrophages and to what extent neurotrophins themselves modulate macrophage activation, in a model of primary adult monocyte-derived macrophage. Our data indicate that macrophages express neurotrophin and neurotrophin receptor genes differentially, and respond to cell stimulation by specific inductions. Neurotrophins did not modify the antigen-presenting capacities of macrophages or their production of proinflammatory cytokines, but somehow skewed their activation phenotype. In contrast, NGF clearly increased CXCR-4 expression in macrophage and their chemotactic response to low CXCL-12 concentration. The differential effect of specific macrophage stimuli on neurotrophin expression, in particular NGF and NT-3, and the specific enhancement of CXCR-4 expression suggest that neurotrophins might participate in tissue-healing mechanisms that should be investigated further in vivo.
Naturally occurring Bruton's tyrosine kinase mutations have no dominant negative effect in an X-linked agammaglobulinaemia cellular model
Authors: Pérez de Diego R , López-Granados E , Rivera J , Ferreira A , Fontán G , Bravo J , García Rodríguez Ma C , Bolland S
Published: July 2010

X-linked agammaglobulinaemia (XLA) is characterized by absence of mature B cells because of mutations in the Bruton's tyrosine kinase (Btk) gene. Btk-deficient early B cell precursors experience a block in their differentiation potentially reversible by the addition of an intact Btk gene. Btk expression was measured in 69 XLA patients with 47 different mutations and normal expression was detected in seven. We characterized these Btk mutant forms functionally by transfection into a lymphoma cell line that lacks endogenous Btk expression (Btk−/− DT40 cells) and analysed the calcium flux in response to B cell receptor stimulation. To test whether co-expression of a mutated form could compromise the function of the intact Btk transfection, studies in wild-type (WT) DT40 cells were also performed. Study reveals that none of the seven Btk mutants analysed was able to revert the absence of calcium mobilization upon IgM engagement in Btk−/− DT40 cells, as does intact Btk. In addition, calcium mobilization by anti-IgM stimulation in DT40 Btk+/+ cells was unaffected by co-expression with Btk mutants. These results suggest that gene addition would be feasible not only for patients with XLA and mutations that prevent Btk expression, but for those with expression of a mutant Btk.
Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model
Authors: Joseph A , Munroe K , Housman M , Garman R , Richards S
Published: July 2010

Clinical investigations of recombinant human acid α-glucosidase for the treatment of Pompe disease often reveal the appearance of therapy-specific antibodies. These antibodies could potentially interfere with recombinant human acid α-glucosidase efficacy and induce immunological consequences. Several immunosuppressive agents, including methotrexate, mycophenolate mofetil and cyclosporin A with azathioprine, were evaluated for their potential to induce immune tolerance to recombinant human acid α-glucosidase. Methotrexate was the only agent that reduced recombinant human acid α-glucosidase-specific antibody responses in acid α-glucosidase knock-out mice. A 3-week, low-dose methotrexate regimen controlled recombinant human acid α-glucosidase-specific antibody levels throughout 8 months of weekly recombinant human acid α-glucosidase treatment. The success of this methotrexate regimen appears to require methotrexate administration within the first 24 h of recombinant human acid α-glucosidase treatment. In an attempt to understand the benefit of methotrexate within the first day of recombinant human acid α-glucosidase administration, the immune response 24 h following intravenous recombinant human acid α-glucosidase treatment was investigated. A consistent expansion of peritoneal B1 B cells was observed. Control over this B1 B cell response may be part of the complex mechanism of action of methotrexate-induced immune tolerance.
Immunomodulatory effects of plasminogen activators on hepatic fibrogenesis
Authors: Higazi A A , El-Haj M , Melhem A , Horani A , Pappo O , Alvarez C E , Muhanna N , Friedman S L , Safadi R
Published: July 2010

Tissue-type plasminogen activators (tPA) and urokinase-type plasminogen activators (uPA) are involved in liver repair. We examined the potential immunomodulatory actions of uPA, tPA and uPA-receptor (uPAR) in carbon-tetrachloride-induced hepatic fibrosis in wild-type (WT), tPA−/−, uPA−/− and uPAR−/− mice. Carbon-tetrachloride treatment increased fibrosis in four groups but significantly less in three knock-out models. Serum cytokines and intrahepatic T cells elevated significantly following fibrosis process in WT animals but not in the knock-out groups. In culture, uPA increased lymphocyte proliferation significantly in WT and uPA−/− but not uPAR−/− animals. Following uPA exposure in vivo, there was CD8 predominance. To isolate uPA's effect on lymphocytes, WT mice were irradiated sublethally and then reconstituted with WT or uPA−/− lymphocytes. In these animals fibrosis was decreased and T cells were reduced in the uPA−/− recipients. Based on these data we postulate that plasminogen activators affect fibrosis in part by liver-specific activation of CD8 subsets that govern the fibrogenic activity of hepatic stellate cells.
Inhibition of casein kinase 2 enhances the death ligand- and natural kiler cell-induced hepatocellular carcinoma cell death
Authors: Kim H-R , Kim K , Lee K-H , Kim S J , Kim J
Published: July 2010

Recent studies have shown that the inhibition of casein kinase 2 (CK2) sensitizes many cancer cells to Fas ligand- and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. However, it has not been demonstrated directly whether CK2 inhibition can also enhance the cytotoxicity of natural killer (NK) cells, which actually use the death ligands to kill cancer cells in vivo. To address whether NK cell-mediated cancer cell death is affected by the inhibition of CK2, we first checked whether the death ligand-induced apoptosis of hepatocellular carcinoma cells (HCCs) and HeLa were affected by CK2 inhibition. We then investigated the effect of CK2 inhibition on NK cytotoxicity against HCCs and HeLa cells and its mechanistic features. Inhibition of CK2 by emodin increased the apoptotic cell death of HepG2, Hep3B and HeLa when the cancer cell lines were treated with a soluble form of recombinant TRAIL or an agonistic antibody of Fas. This phenomenon appeared to be correlated with the expression level of death receptors on the cancer cell surface. More interestingly, the inhibition of CK2 also greatly increased the NK cell-mediated cancer cell killing. The NK cytotoxicity against the cancer cells increased about twofold when the target cells were pretreated with a specific CK2 inhibitor, emodin or 4,5,6,7-tetrabromobenzotriazole. Furthermore, the increase of the NK cytotoxicity against cancer cells by CK2 inhibition was granule-independent and mediated possibly by the death ligands on the NK cell surface. This suggests that CK2 inhibitors could be used to enhance the cytotoxicity of NK cells and consequently increase host tumour immunity.
A novel, helminth-derived immunostimulant enhances human recall responses to hepatitis C virus and tetanus toxoid and is dependent on CD56+ cells for its action
Authors: MacDonald A J , Libri N A , Lustigman S , Barker S J , Whelan M A , Semper A E , Rosenberg W M
Published: July 2010

We have described previously an immunostimulant derived from Onchocerca volvulus, the helminth parasite that causes onchocerciasis. Recombinant O. volvulus activation-associated secreted protein-1 (rOv-ASP-1) was a potent adjuvant for antibody and cellular responses to protein, polypeptide and small peptide antigens. Our aims were to determine whether rOv-ASP-1 is immunostimulatory for human peripheral blood mononuclear cells (PBMC) and, if so, whether it could augment cellular responses against human pathogen antigens in vitro. Cytokines from rOv-ASP-1-stimulated human PBMC were measured by a fluorescence activated cell sorter-based multiplex assay. Recall responses of normal healthy donor (NHD) and chronic hepatitis C virus (c-HCV)-infected patient PBMC to tetanus toxoid (TT) or HCV core (HCVco) antigen, respectively, were measured by interferon-γ enzyme-linked immunospot assays. Interferon-γ was the predominant cytokine induced by rOv-ASP-1. 77·3% of NHD anti-TT and 88·9% of c-HCV anti-HCVco responses were enhanced by rOv-ASP-1. The immunostimulant effect was dependent upon contact between CD56+ and CD56– fractions of PBMC. We have described a helminth-derived protein that can act as an immunostimulant for human recall responses in vitro to TT and, perhaps more importantly, HCV antigens in patients with chronic HCV infection. Our longer-term goal would be to boost anti-viral responses in chronic infections such as HCV.
Involvement of innate immunity in the pathogenesis of intestinal Behçet's disease
Authors: Nara K , Kurokawa M S , Chiba S , Yoshikawa H , Tsukikawa S , Matsuda T , Suzuki N
Published: July 2010

The involvement of excessive T helper 1 (Th1) cell functions in the pathogenesis of Behçet's disease (BD) has been reported. We therefore studied Toll-like receptor (TLR)-expressing cells, which play important roles in innate immunity in patients with BD. Peripheral blood mononuclear cells (PBMC) of BD and healthy controls, and tissue specimens of intestinal BD and Crohn's disease (CD) were analysed for messenger RNA (mRNA) and protein expressions by reverse transcription–polymerase chain reaction and immunostaining respectively. PBMC of BD expressed TLR-2 and TLR-4 mRNA almost comparable with healthy controls. Intestinal lesions of BD expressed TLR-2 and TLR-4 mRNA consistently. In contrast, TLR-4 mRNA was expressed preferentially and TLR-2 mRNA was expressed less frequently in CD lesions. In intestinal samples of BD, TLR-2 and TLR-4 mRNA were detected in ileocaecal ulcer lesions, but not in unaffected sites of the same sample, indicating the association of the TLR expression with the disease manifestation of intestinal BD. TLR-2-expressing cells which were simultaneously cluster of distribution (CD)68-positive produced interleukin (IL)-12 in the lesions, indicating the participation of TLR-2-expressing cells in the Th1 skewed responses in vivo. As a possible ligand of TLR-2, in BD self-heat shock protein 60 was expressed in peripheral blood lymphocytes and intestinal tissues. Collectively, TLR-2-expressing cells as well as TLR-4-expressing cells accumulated in the intestinal lesions of BD. IL-12 produced by TLR-2-expressing cells may contribute to the induction of Th1-dominant immune responses in intestinal BD.
Varicella zoster virus glycoprotein E-specific CD4+ T cells show evidence of recent activation and effector differentiation, consistent with frequent exposure to replicative cycle antigens in healthy immune donors
Authors: Malavige G N , Jones L , Black A P , Ogg G S
Published: July 2010

Varicella zoster viru (VZV)-specific T cell responses are believed to be vital in recovery from primary VZV infection and also in the prevention of viral reactivation. While glycoprotein E (gE) is the most abundant and one of the most immunogenic proteins of the virus, there are no data addressing potential T cell epitopes within gE, nor the phenotype of specific T cells. Using interferon gamma enzyme-linked immunospot assays and intracellular cytokine assays, we identified gE-specific immune responses in 20 adult healthy immune donors which were found to be dominated by the CD4+ subset of T cells. We characterized three immune dominant epitopes within gE restricted through DRB1*1501, DRB1*07 and DRB4*01, and used DRB1*1501 class II tetrameric complexes to determine the ex vivo frequency and phenotype of specific T cells. In healthy immune donors, the cells were largely positive for CCR7, CD28 and CD27, but expressed variable CD62L and low levels of cutaneous lymphocyte associated antigen with evidence of recent activation. In summary, we show that circulating gE-specific CD4+ T cells are detected at a relatively high frequency in healthy immune donors and show evidence of recent activation and mixed central and effector memory phenotype. These data would be compatible with frequent exposure to replicative cycle antigens in healthy donors and are consistent with a role for gE-specific CD4+ T cells in the control of viral replication.
Reduced arthritis in MIF deficient mice is associated with reduced T cell activation: down-regulation of ERK MAP kinase phosphorylation
Authors: Santos L L , Dacumos A , Yamana J , Sharma L , Morand E F
Published: July 2010

Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine with many cellular targets in rheumatoid arthritis (RA). MIF has been reported to activate cells via mitogen-activated protein kinase and serine/threonine kinase (AKT or protein kinase B)-dependent signal transduction pathways. Its contribution to T cell activation and signalling in RA is not known. Using MIF −/− mice and a T cell-mediated model of RA, antigen-induced arthritis, we investigated the role of MIF in T cell activation and signalling. Arthritis severity was significantly reduced in MIF −/− mice compared with wildtype mice. This reduction was associated with decreased T cell activation parameters including footpad delayed type hypersensitivity, antigen-induced splenocyte proliferation and cytokine production. Splenocyte proliferation required extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and decreased T cell activation in MIF −/− mice was associated with decreased phosphorylation of ERK1/2 but not AKT. Collectively, these data suggest that MIF promotes antigen-specific immune responses via regulation of ERK phosphorylation in T cells.
Special Anniversary Review: Twenty-five years of human immunodeficiency virus research: successes and challenges
Authors: Weiss R A
Published: July 2010

During 25 years of research since HIV-1 was first identified in Paris, there have been great advances in our understanding of the virus and of the immune system. Practical advances include the early development of diagnostic tests of infection that made blood donation safe, and since 1996, combination anti-retroviral therapy that has great reduced incidence of AIDS in HIV-infected people who have access to the drugs. HIV prevention through behavioural change has been successful, and we do not yet have any safe and efficacious microbicides or vaccines.
Human immunodeficiency virus (HIV)-specific T helper responses fail to predict CD4+ T cell decline following short-course treatment at primary HIV-1 infection
Authors: Fox J , Scriba T J , Robinson N , Weber J N , Phillips R E , Fidler Sarah
Published: July 2010

Early anti-retroviral treatment (ART) in primary human immunodeficiency virus (HIV) infection (PHI) may have unique, restorative immunological and virological benefits which could enhance clinical outcomes. However, the sustainability of these HIV-specific immune responses and their impact on clinical outcome remains unclear. We present a 3-year longitudinal clinical and immunological follow-up of a single-arm, prospective study assessing the long-term impact of a short-course of ART (SCART) during PHI. Twenty-eight subjects with defined PHI received 3 months of SCART at HIV-1 seroconversion. HIV-specific interferon-γ+ CD4+ T cell responses, CD4 cell counts and plasma viral loads were assessed prospectively. Clinical outcome was defined as the time taken from PHI to a fall in CD4 cell counts <350 cells/μl on two or more occasions. Of 28 patients, 25 (89%) had detectable HIV-specific CD4+ helper responses at baseline. Five of 11 (45%) patients had preserved HIV-specific CD4+ responses 3 years after stopping SCART. Neither the presence nor magnitude of HIV-1-specific T helper responses either at baseline or 3 years following SCART cessation predicted clinical outcome. Rebound viraemia associated with stopping SCART did not diminish HIV-1-specific CD4+ responses. Long-term (>3 years) preservation of virus-specific CD4+ cells occurred in 45% of patients receiving SCART in PHI. There was no correlation between either the presence or magnitude of these responses and clinical outcome.
The profile of gene expression and role of nuclear factor kappa B on glomerular injury in rats with Thy-1 nephritis
Authors: Wang H , Jiang X M , Xu J H , Xu J , Tong J X , Wang Y W
Published: July 2010

Mesangioproliferative glomerulonephritis (MsPGN) is a disease of high incidence in humans. Rats with Thy-1 nephritis (Thy-1 N) are used as an animal model for studying MsPGN. Although several studies have demonstrated that many pathological factors could cause the injury of glomerular mesangial cells (GMCs) in Thy-1 N, changes of profile and the molecular mechanism of the disease (i.e. the role of transcription factors) at intervals remain unclear. The purpose of this study was to identify the changes in gene expression profile and to observe the role of nuclear factor kappa B (NF-κB) on the pathological change of renal tissue in Thy-1 N rats. Our results showed that the pathological changes of GMCs in Thy-1 N included three phases: apoptosis (40 min), necrosis (24 h) and proliferation (7 days). Concomitantly, at 40 min and on day 7, the up-regulation of 341 genes and 250 genes were observed, while 392 genes and 119 genes were down-regulated in Thy-1 N. Expression of interleukin (IL)-1β, IL-6, proliferating cell nuclear antigen, α-smooth muscle actin, collagen type IV and excretion of urinary protein was increased in rats with Thy-1 N and decreased in pyrrolidine dithiocarbamate-treated rats with Thy-1 N. These data indicated that the significant changes in the gene profile were coupled with the pathological changes of Thy-1 N, and activation of NF-κB may contribute to the pathogenesis of GMCs apoptosis, proliferation, extracelluar matrix accumulation and proteinuria in Thy-1 N.
99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Evolution of adaptive immunity in vertebrates
Authors: Cooper M D
Published: July 2010

Adaptive immunity has been defined, principally through studies of avian and mammalian species, as the ability to mount specific immune responses to a virtually unlimited variety of antigens. A key feature of an adaptive immune system is the ability to remember previous encounters with antigens and to achieve a more rapid, heightened response on secondary encounter. Adaptive immune systems featuring an enormous anticipatory receptor diversity and specific memory have been defined only in vertebrates. Surprisingly, the adaptive immune systems in jawless and jawed vertebrates employ very different types of antigen receptors. This evolutionary inventiveness suggests that adaptive immunity provided additional fitness value over the previously existing innate immune mechanisms.
99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Symbionts and immunopathology in chronic diseases: insights from evolution
Authors: Ewald P W
Published: July 2010

Immunological aetiologies of disease are not generally well understood, but have been attributed to intrinsic immunological imbalances, infectious triggers or persistent infections. Evolutionary considerations lead to the formulation of three feasible categories of immunopathology for common diseases. One category of hypotheses presumes that the immune system is exposed to environmental conditions to which the individual is not well adapted. One hypothesis within this category, often referred to as the hygiene hypothesis, proposes that new more hygienic environmental conditions have generated compositions of symbionts that differ from those to which humans have been adapted. A second category of hypotheses proposes that infectious agents act as triggers of immunopathology by shifting the immune system into a self-destructive state. A third category proposes that infectious agents keep the immune in a self-destructive state by causing persistent infections. To evaluate disease causation rigorously and to determine the appropriate interventions, these three categories of causation need to considered for every disease that involves immunopathology. Assessment of the progress in understanding oncogenesis and other chronic diseases emphasizes the value of such integrated assessments.
99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Triggering of autoimmune diseases by infections
Authors: Getts M T , Miller S D
Published: July 2010

Human autoimmune diseases, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE), are linked genetically to distinct major histocompatibility complex (MHC) class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk suggest a critical role for environmental factors in the triggering of these autoimmune diseases. Among potential environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. This review will discuss human autoimmune diseases with a potential viral cause, and outline potential mechanisms by which pathogens can trigger autoimmune disease as discerned from various animal models of infection-induced autoimmune disease.
Invasive pattern grading score designed as an independent prognostic indicator in oral squamous cell carcinoma
Authors: Chang Yun‐Ching , Nieh Shin , Chen Su‐Feng , Jao Shu‐Wen , Lin Yu‐Lu , Fu Earl
Published: July 2010

Chang Y‐C, Nieh S, Chen S‐F, Jao S‐W, Lin Y‐L & Fu E (2010) Histopathology 57, 295–303 Invasive pattern grading score designed as an independent prognostic indicator in oral squamous cell carcinoma

Aims:  To test the validity of an invasive pattern grading score (IPGS) developed for oral squamous cell carcinoma (OSCC) as a prognostic indicator and to elucidate the relationship between the IPGS and clinical parameters.

Methods and results:  The IPGS was applied to a total of 153 cases of OSCC. There were significant correlations between IPGS and distant metastasis (P = 0.01) or recurrence (P = 0.001). However, there were no significant correlations between IPGS and gender, age, size or extent, location, status of lymph node metastasis, clinical staging, or histological grading. Cases of OSCC with higher IPGS were associated with poor patient survival (P < 0.001) and higher probability of tumour recurrence (P = 0.001). Intraobserver (κ = 0.74) and interobserver agreement (κ = 0.67) were very satisfactory.

Conclusions:  Our study confirms the validity of the IPGS, an indicator that is simple and easy to use. IPGS not only provides histological assessment of biological behaviour, but also offers an independent prognostic factor that may influence the treatment of OSCC.
Nature and orientation of ice in frozen fish
Authors: AITKEN A.
Published: July 2010

The ice component of frozen fish muscle has been examined by X‐ray diffraction. Only the common hexagonal form was observed, but line intensities indicated strong orientation of the crystallites. The c‐axis is shown to be perpendicular to the direction of freezing; the muscle fibre direction does not appear to affect the direction of orientation to a noticeable extent.
An equation for the activity coefficients and equilibrium relative humidities of water in confectionery syrups
Authors: NORRISH R. S.
Published: July 2010

An apparatus is described for determining the equilibrium relative humidity (e.r.h.) of confectionery syrups and the results obtained are compared with those of other workers. The identity of e.r.h. with the thermodynamic activity is pointed out and an equation for the activity coefficient as a function of concentration is derived. The agreement between e.r.h. values calculated by means of this equation and experimental results is demonstrated and some of the advantages of the use of equations of this type are discussed, including the ability to draw significant conclusions about the nature of the solvent‐solute interaction.
Sequential procedures for triangular and paired comparison tasting tests
Authors: STEINER E. H.
Published: July 2010

The necessary number of tasting tests which must be carried out in the comparison of two samples by triangular tests or paired comparisons is considered in relation to: (1) the risk of stating that the samples are different when they are in fact not distinguishable, (2) the risk of stating the samples are identical when a distinguishable difference really exists, and (3) the degree of ‘difference’ it is desired to distinguish.

Sequential procedures are put forward which enable a decision to be reached relatively quickly, with 1 in 20 risks of error, when the two samples either are identical or differ by a defined amount. Separate tables are given for difference testing and quality testing. In cases where the sequential test would be lengthy the procedures terminate the tests after an amount of tasting which only slightly increases the risk of error.
The glassy state in certain sugar‐containing food products *
Authors: WHITE G. W. , CAKEBREAD S. H.
Published: July 2010

A review is given of the literature on organic glasses with special reference to sugar glasses. The amorphous sugar glasses in boiled sweets, milk powder, ice cream and certain freeze‐dried products are then discussed. Breakdown of these sugar glasses can lead to defects in all four cases.
A new method for counting bold and blind seeds in raspberry jam and for computing blindness rate constants
Authors: DAKIN J. C. , TAMPION J.
Published: July 2010

A new technique and cell for counting bold and blind seeds in raspberry jam is described. Using this method it was found that the rate at which seeds become blind in a jam follows a logarithmic course. This is analogous to the thermal death rate for bacteria and consequently the standard mathematical concepts for dealing with this phenomenon may equally be applied to blindness development. An expression Ds, equivalent to the decimal reduction time for bacteria, is used to compare the rates of blindness development in experimental jams. This represents the time in weeks for 90% of the seeds to become blind. The new methods are illustrated by results obtained from experimental jams.
Bending, shrinkage and texture of cod frozen at sea
Authors: LOVE R. M.
Published: July 2010

Newly‐caught cod were fixed in bent positions with various degrees of curvature during the onset and resolution of rigor mortis. It was found that even in those bent in a complete circle, head and tail touching, there was no significant denaturation of the proteins, neither was the texture found to be tough on tasting. The importance of the results in relation to freezing fish at sea is discussed.
The use of tasters for investigating cold storage deterioration in frozen fish
Authors: LOVE R. M.
Published: July 2010

Frozen cod cold‐stored at −14°C were tasted for texture changes by an untrained panel, using a simple comparison technique that did not require the use of memory. It was found that the fish had to be kept for about 3 1/2 weeks at −14°C before the tasters could clearly detect toughening, and a nomogram, constructed from objective data, is given to show the equivalent times at other temperatures.
The effect of sodium chloride, potassium nitrate and sodium nitrite on the recovery of heated bacterial spores *
Authors: ROBERTS T. A. , INGRAM M.
Published: July 2010

The ability of aerobic and anaerobic spores, after various degrees of heating, to produce macrocolonies in media containing different concentrations of sodium chloride, potassium nitrate and sodium nitrite has been examined. The effect of different heat treatments, roughly from F0= 0.0015 to F0= 1.5, on the inhibitory levels of these curing ingredients, showed that the more severe treatments were capable of rendering surviving spores considerably more sensitive to subsequent inhibition by concentrations of the order found in cured meats. To produce this effect, less heating was needed with two Bacillus strains than with three of Clostridium. Sodium chloride and potassium nitrate had quantitatively similar effects. The inhibitory effect of sodium nitrite increased roughly ten‐fold from pH 7 to pH 6.