bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis
Authors: KEHLEN A , THIELE K , RIEMANN D , LANGNER J 
Published: March 2003

SUMMARYInterleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4+ CD45RO+ memory T cells. Overproduction of IL-17 was detected in the synovium of patients with rheumatoid arthritis (RA) compared to patients with osteoarthritis. In contrast to the restricted expression of IL-17, the IL-17 receptor (IL-17R/CDw217) is expressed ubiquitously. Using a real-time RT-PCR assay, we detected similar absolute levels of IL-17R mRNA expression in fibroblast-like synoviocytes (SFC) from patients with RA (mean 9 pg/μg total RNA; ranged from 0·1 pg to 96 pg IL-17R mRNA/μg total RNA) compared to synoviocytes of non-RA patients. Analysis of the IL-17R surface expression confirmed the results obtained for IL-17R mRNA expression. Exposure of SFC to IL-17 led to a mRNA induction of CXC chemokines IL-8, GRO-α and GRO-β. An anti-IL-17 antibody blocked these effects of IL-17. The MAPK p38 appears necessary for the regulation of IL-8, GRO-α and GRO-β expression as shown by inhibition with SB203580. The inhibitors genistein (tyrosine kinase inhibitor) and calphostin C (inhibitor of protein kinase C) reduced significantly the IL-17-stimulated mRNA expression of IL-8, GRO-α and GRO-β in SFC, whereas PD98059 (inhibitor of MEK-1/2) was without effect. Pharmacological drugs used in therapy of RA, such as cyclosporin and methotrexate, induced a fourfold increase of IL-17R mRNA expression and augmented the IL-17-stimulated IL-8 expression. Our results support the hypothesis that IL-17/IL-17R may play a significant role in the pathogenesis of RA contributing to an unbalanced production of cytokines as well as participating in connective tissue remodelling.
Elevated monocytic IL-12 and TNF-αproduction in Wegener's granulomatosis is normalized by cyclophosphamide and corticosteroid therapy
Authors: LAMPRECHT P , KUMANOVICS G , MUELLER A , CSERNOK E , KOMOCSI A , TRABANDT A , GROSS W L , SCHNABEL A 
Published: March 2003

SUMMARYWegener's granulomatosis (WG) is characterized by a predominance of the type 1 T-helper cell (Th1) response. We have studied monocytic cytokine expression in untreated patients and in patients who did not respond to prior methotrexate or trimethoprim-sulphamethoxazole therapy, i.e. patients with active disease. Intracytoplasmic IL-12 and TNF-α expression was significantly increased in WG compared with healthy controls. IL-8 expression was not increased. Two and 12 weeks of daily standard oral cyclophosphamide and corticosteroid (CYC + GC) treatment induced a stable remission of the disease. Elevated IL-12 and TNF-α expression of monocytes was normalized. The active metabolite of CYC was shown to down-regulate IL-12 mRNA in vitro. Monocytic cytokines, especially IL-12, may have a role in the early determination and skewing of the immunoregulatory response towards a Th1 profile. It appears that CYC + GC exerts its effect by normalizing the Th1-driving cytokine pattern, and CYC may maintain this mode of action. Normalization of the skewed cytokine pattern may be a prerequisite and an indicator of inducing a remission in WG.
Highly active antiretroviral therapy restores in vitro mitogen and antigen-specific T-lymphocyte responses in HIV-1 perinatally infected children despite virological failure
Authors: PERUZZI M , AZZARI C , GALLI L , VIERUCCI A , DE MARTINO M 
Published: March 2003

SUMMARY
To analyse the effect of highly active antiretroviral therapy (HAART) on T-lymphocyte functions we selected seven HIV-1 perinatally infected children (CDC immunological category 1 or 2) who had neither a fall in their plasma HIV-1 RNA levels nor a significant rise in CD4+ lymphocyte counts while receiving HAART. Clinical signs and symptoms were monitored monthly. Plasma viral load, CD4+, CD8+, CD19+ lymphocyte counts and in vitro T-lymphocyte proliferative responses to mitogens (anti-CD3, phytohaemoagglutinin, concanavalin A and pokeweed mitogen) and recall antigens (Candida albicans and tetanus toxoid) were tested at baseline and after 1, 3, 6 and 12 months of HAART. Twenty-two healthy age-matched children were studied as controls. A gain in body weight, no worsening of the disease and no recurrence of opportunistic infections were observed. At baseline, the majority of the children had low responses to mitogens, and all of them had a defective in vitro antigen-specific T-lymphocyte response (&lt;2 standard deviations below the mean result for controls). During HAART, a significant increase in the response to mitogens and antigens was observed in all the patients. The T-lymphocyte response was restored more consistently against antigens to which the immune system is constantly exposed (Candida albicans, baseline versus 12 months: P &lt; 0·001) compared with a low-exposure antigen (tetanus toxoid, baseline versus 12 months: P &lt; 0·01). HAART restores in vitro T-lymphocyte responses even in the absence of a significant viral load decrease and despite any significant increase in CD4+ lymphocyte counts. It implies that a direct mechanism might be involved in the overall immune recovery under HAART.
Transforming growth factor-β expression in human retinal pigment epithelial cells is enhanced by Toxoplasma gondii: a possible role in the immunopathogenesis of retinochoroiditis
Authors: NAGINENI C N , DETRICK B , HOOKS J J 
Published: March 2003

SUMMARY
Retinochoroiditis caused by Toxoplasma gondii infection results in inflammation and necrosis of the retina. We have used human retinal pigment epithelial cultures (HRPE) as an in vitro model to investigate the role of TGF-β in T. gondii-induced retinochoroiditis. RT-PCR analyses showed enhanced steady state levels of TGF-β1 and TGF-β2 mRNA in T. gondii-infected HRPE. Uninfected HRPE secrete TGF-β1 in a latent form while 10–30% of the secreted TGF-β2 was in the active form. T. gondii infection induced a significant increase (P &lt; 0·01) in total TGF-β1 and TGF-β2 secretion by HRPE. In addition, soluble extracts of T. gondii (ST) stimulated secretion of both TGF-β1 and TGF-β2 significantly (P &lt; 0·01). Interestingly, T. gondii infection as well as ST of the parasites completely inhibited secretion of the active form of TGF-β2. Studies evaluating the effect of TGF-β on T. gondii replication in HRPE revealed that TGF-β enhanced parasite replication. The interactions between host retinal cells and T. gondii may play an active role in the pathogenesis of retinochoroiditis.
Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia
Authors: SCHUBERT R , REICHENBACH J , ZIELEN S 
Published: March 2003

SUMMARYChronic sinopulmonary infections that are associated with immunodeficiency are one of the leading causes of death in the multi-systemic disease ataxia telangiectasia (AT). Immunological investigations of AT patients revealed a broad spectrum of defects in the humoral and the cellular immune system. Based on their important role in host defence the aim of our study was an extensive analysis of cell distribution and function of CD4+ and CD8+ T lymphocytes and NK cells. We found that naive (CD45RA+) CD4+ lymphocytes, as well as CD8+/CD45RA+ lymphocytes, are decreased, whereas NK cells (CD3−/CD16+CD56+) are significantly elevated in AT patients. In our culture system proliferation and cytokine production was normal in purified memory (CD45RO+) lymphocytes after stimulation with phorbol-12,13-dibutyrate (PBu2) and after PHA activation, indicating that differences in proliferation and cytokine production are due solely to reduced numbers of CD45RA+ lymphocytes. However, activation, and especially intracellular interferon production of AT lymphocytes, seem to follow different kinetics compared to controls. In contrast to polyclonal activation, stimulation via the T cell receptor results consistently in a reduced immune response. Taken together, our results suggest that deficiency of immunocompetent cells and an intrinsic immune activation defect are responsible for the immunodeficiency in AT.
Diversity and dynamics of the T-cell response to MBP in DR2+ve individuals
Authors: MAZZA G , PONSFORD M , LOWREY P , CAMPBELL M J , ZAJICEK J , WRAITH D C 
Published: March 2003

SUMMARYIt is generally accepted that multiple sclerosis (MS) is mediated by autoreactive T cells and that myelin basic protein (MBP) is one of the target autoantigens. The T-cell response to MBP has been analysed extensively, largely through the use of T-cell lines (TCL) and T-cell clones (TCC), and to date, three immunodominant regions (13–32, 84–103 and 144–163) have been described. However, given that TCL may represent a skewed pattern of peptide reactivity, we have developed a kinetic response assay in which the proliferation of peripheral blood mononuclear cells (PBMC) from MS patients and healthy individuals was measured directly against a panel of peptides spanning the full length of human MBP. Furthermore, PBMC from each subject were tested three times over the course of 18 months. A high proportion of MS patients exhibited a significant response to eight MBP regions (1–24, 30–54, 75–99, 90–114, 105–129, 120–144, 135–159 and 150–170). TCC were subsequently generated from MS subjects and were used to further define the epitope recognized in each case. Overall, normal individuals recognized significantly fewer peptides. In addition, we noted that the T-cell recognition of any one peptide can fluctuate, appearing at one time point, regressing, and subsequently reappearing at a later date. This study provides new insight into the recognition profile and dynamics of myelin-antigen-specific T cells in MS.
Longitudinal study of intracellular T cell cytokine production in infants compared to adults
Authors: BUCK R H , CORDLE C T , THOMAS D J , WINSHIP T R , SCHALLER J P , DUGLE J E 
Published: March 2003

SUMMARYIntracellular cytokine production in lymphocytes obtained longitudinally from 325 healthy infants aged 2–12 months was compared with adult lymphocytes using four-colour flow cytometry. Peripheral blood samples (180 microlitres) were stimulated with phorbol 12-myristate 13-acetate, ionomycin and brefeldin A to induce production and intracellular accumulation of cytokines. The method was validated by assessing reproducibility, repeatibility, ruggedness (i.e. fresh versus day-old blood samples), precision, linearity and sensitivity. Among infants, the number and percentage of T lymphocytes (helper/inducer T cell subsets and cytotoxic/suppressor T cell subsets) producing IFN-γ (type 1) and IL4 (type 2) increased over the first year of life but remained significantly lower than levels found in adults. In both infants and adults more CD4− T cells than CD4+ T cells were induced to make IFN-γ. Infant Th1/Th2 ratios revealed modest Th1-skewed (predominant) profiles compared to adults, which were 5–10 times higher. Infant Tc1/Tc2 ratios revealed Tc1-skewed responses which were equal to adult ratios by age 12 months. At 12 months infant Th2 responses were closer to adult levels than were Th1 cells. Intracellular cytokine detection by flow cytometry is a rapid, sensitive, rugged and precise method to characterize immune status changes over time.
Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected byCryptosporidium parvum
Authors: PONNURAJ E M , HAYWARD A R 
Published: March 2003

SUMMARYAn increase in mRNA levels for TNF and Tnfrsf1 in the bile ducts of Tnfsf5–/–(CD40 ligand or CD154 knockout) mice developing cholangitis following infection by Cryptosporidium parvum (CP) is accompanied by staining for TNFα in areas of inflammation. To determine whether TNF contributed to the bile duct damage seen in chronically-infected animals, we bred B6 mice with disrupted genes for Tnfrsf1a, Tnfrsf1b and Tnfsf5. Following CP infection, the Tnfsf5–/– Tnfrsf1a & 1b–/– mice were spared from cholangitis, even though their intestinal and bile duct infection by CP persisted. Mice with disruptions of Tnfsf5, and either Tnfrsf1a or Tnfrsf1b, developed bile duct sclerosis similar to that seen in CD40 and Tnfsf5 knockouts. Our data indicate that signalling through either TNF receptor is sufficient for the bile duct damage that follows chronic CP infection in mice, with disruption of the Tnfsf5 molecule.
Leptin receptor (Ob-R) expression is induced in peripheral blood mononuclear cells byin vitroactivation andin vivoin HIV-infected patients
Authors: SÁNCHEZ-MARGALET V , MARTÍN-ROMERO C , GONZÁLEZ-YANES C , GOBERNA R , RODRÍGUEZ-BAÑO J , MUNIAIN M A 
Published: March 2003

SUMMARYLeptin, the Ob gene product, is an adipocyte hormone that centrally regulates weight control. In addition, other effects of leptin in peripheral tissues have been described. Thus, leptin has been found to regulate reproduction, haematopoiesis and immune function. We have found recently that leptin has a stimulatory effect on human peripheral blood mononuclear cells (PBMC). Monocytes are activated by leptin alone whereas T lymphocytes need a suboptimal stimulus of PHA or ConA before further activation by leptin. These effects are mediated by the long isoform of the leptin receptor, which has been shown to trigger signalling in PBMC. In fact, we have found that human leptin stimulates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in PBMC. In order to assess possible regulation of the long isoform of the leptin receptor (Ob-R) in mononuclear cells upon activation, we have studied the expression of Ob-R by RT-PCR and Western blotting in PBMC activated in vitro by PHA or ConA and in vivo in HIV-infected patients. We have found that in vitro activation and in vivo HIV infection correlates with an increase in leptin receptor expression in PBMC. Moreover, the leptin receptor is tyrosine phosphorylated in PBMC from HIV-infected patients, suggesting that the leptin receptor is activated. These results are consistent with the suggested role of leptin in modulating the immune response.
Interferon-αinduces interleukin-18 binding protein in chronic hepatitis C patients
Authors: KASER A , NOVICK D , RUBINSTEIN M , SIEGMUND B , ENRICH B , KOCH R O , VOGEL W , KIM S H , DINARELLO C A , TILG H 
Published: March 2003

SUMMARYInterleukin-18 (IL-18), derived from macrophages and Kupffer cells, is the central pro-inflammatory cytokine leading to experimental liver failure. IL-18 binding protein (IL-18BP) is a circulating protein that binds IL-18 and neutralizes its activity. Since IL-18 production is increased in chronic HCV infection, we asked whether IFN-α might act on the IL-18/IL-18BP system in HCV patients. IL-18BP, total and free IL-18 plasma levels were determined in 13 HCV patients receiving 1 × 107 IU IFN-α subcutaneously daily for 28 days. The in vitro effects of IFN-α on macrophage IL-18BP and IL-18 were studied by enzyme-linked immunosorbent assays and Northern analysis. IFN-α administration increased IL-18BP plasma levels 3·24 fold 24 h after institution of therapy, resulting in a 67·4% reduction of free IL-18. Total IL-18 levels decreased from day +24 on. In vitro, IFN-α diminished IL-18 release from macrophages of healthy volunteers and chronic HCV patients. On top of its inhibitory effects on IL-1 and TNF-α release, IFN-α also exerts its anti-inflammatory action in vivo by induction of IL-18BP. These anti-inflammatory properties might account – together with its antiviral action – for its clinical efficacy in chronic hepatitis C.
Novel promiscuous HLA-DQ HIV Nef peptide that induces IFN-γ-producing memory CD4+T cells
Authors: PANCRÉ V , GEORGES B , ANGYALOSI G , CASTELLI F , DELANOYE A , DELACRE M , HACHULLA E , MAILLERE B , BOUZIDI A 
Published: March 2003

SUMMARYWe describe the highly conserved sequence 56–68 of the HIV Nef protein as the first promiscuous HLA-DQ HIV-derived peptide. The Nef peptide exhibits an albeit rare capacity to bind 6 different HLA-DQ molecules whereas no binding is observed with the 10 HLA-DR molecules tested. In agreement with these data, after immunization with the Nef peptide, HLA-DQ transgenic Aβ° mice display a vigorous cellular and humoral response while the specific immune response of HLA-DR expressing mice is minimal. The promiscuous potentiality of the Nef 56–68 peptide in humans has been confirmed by ex vivo immunization experiments with CD4+ T cells from 14 healthy donors expressing different HLA genotypes. Nef 56–68 specific CD4+ T cells rapidly acquire a memory cell phenotype and are characterized by the preferential usage of the TCR Vβ 6·1 gene segment and predominant production of IFN-γ. Taken together, these data indicate that the Nef 56–68 peptide constitutes an attractive component of vaccines aiming at inducing or enhancing HIV-specific T cell immunity.
Intranasal delivery of a truncated recombinant human SP-D is effective at down-regulating allergic hypersensitivity in mice sensitized to allergens ofAspergillus fumigatus
Authors: STRONG P , REID K B M , CLARK H 
Published: March 2003

SummaryC57BL/6 mice were sensitized to Aspergillus fumigatus 1-week culture filtrate, which is rich in the non-glycosylated allergen Asp f1, a major allergen in allergic bronchopulmonary aspergillosis (ABPA). A comparison of the effect of treatment of allergen challenged mice by intranasal administration of a 60-kDa truncated recombinant form of human SP-D (rfhSP-D) or recombinant full length SP-A (rhSP-A) was undertaken. Treatment with rfhSP-D produced significant reduction in IgE, IgG1 and peripheral blood eosinophilia and treatment with rfhSP-D, but not rhSP-A resulted in a significant reduction in airway hyperresponsiveness as measured by whole body plethysmography. Lung histology revealed less peribronchial lymphocytic infiltration in mice treated with rfhSP-D. Intracellular cytokine staining of spleen homogenates showed increases in IL-12 and IFN-γ and decrease in IL-4. The level of endogenous mouse SP-D was elevated sixfold in the lungs of sensitized mice and was not affected by treatment with rfhSP-D. Taken with our previous studies, with a BALB/c mouse model of ABPA using a 3-week A. fumigatus culture filtrate, the present results show that rfhSP-D can suppress the development of allergic symptoms in sensitized mice independent of genetic background and using a different preparation of A. fumigatus allergens.
Inhibition of experimental autoimmune uveoretinitis by systemic and subconjunctival adenovirus-mediated transfer of the viral IL-10 gene
Authors: DE KOZAK Y , THILLAYE-GOLDENBERG B , NAUD M-C , VIANA DA COSTA A , AURIAULT C , VERWAERDE C 
Published: March 2003

SummaryPathological ocular manifestations result from a dysregulation in the balance between proinflammatory type 1 cytokines and regulatory type 2 cytokines. Interleukin-10 (IL-10) is an anti-inflammatory cytokine with potent immunosuppressive effects. We have examined the efficiency of viral IL-10 adenovirus (Ad-vIL-10)-mediated gene transfer on experimental autoimmune uveoretinitis (EAU) induced in mice and rats by purified retinal autoantigens, respectively, interphotoreceptor binding protein (IRBP) and S-antigen (S-Ag). B10-A mice that received a single unilateral injection of Ad-vIL-10 in the retro-orbital sinus venosus performed 1 day before immunization with IRBP in the footpads showed high levels of circulating vIL-10 in their sera and a significant reduction in pathological ocular manifestations. Lower levels of IFN-γ and IL-2 were found in cellular supernatants from IRBP-stimulated splenic cells in these treated mice. The local effect on ocular disease of vIL-10 was neutralized completely by injection of a monoclonal anti-vIL-10 antibody, demonstrating the specificity of the treatment. To determine whether the transfer of the vIL-10 gene within the periocular tissues of the eye could prevent acute EAU, a subconjunctival injection of Ad-vIL-10 was performed in Lewis rats simultaneously with S-­antigen in the footpads. This injection determined in situ vIL-10 expression with very low circulating vIL-10 and led to a significant reduction of EAU without affecting the systemic immune response. The present results suggest that Ad-mediated gene transfer resulting in systemic and local expression of vIL-10 provide a promising approach for the treatment of uveitis.
The scavenger receptor, cysteine-rich domain-containing molecule gp-340 is differentially regulated in epithelial cell lines by phorbol ester
Authors: KANG W , NIELSEN O , FENGER C , MADSEN J , HANSEN S , TORNOE I , EGGLETON P , REID K B M , HOLMSKOV U 
Published: March 2003

SummaryGp-340 is a glycoprotein belonging to the scavenger receptor cysteine rich (SRCR) group B family. It binds to host immune components such as lung surfactant protein D (SP-D). Recent studies found that gp-340 interacts directly with pathogenic microorganisms and induces their aggregation, suggesting its involvement in innate immunity. In order to investigate further its potential immune functions in the appropriate cell lines, the expression of gp-340 in four conventional immune cell lines (U937, HL60, Jurkat, Raji), and two innate immune-related epithelial cell lines (A549 derived from lung and AGS from stomach), was examined by RT-PCR and immunohistochemistry. The resting immune cell lines showed weak or no gp-340 mRNA expression; while the two epithelial cell lines expressed gp-340 at much higher level, which was differentially regulated by phorbol myristate acetate (PMA) treatment. In the A549 cells, gp-340 was up-regulated along with the PMA-induced proinflammatory expression of both IL-6 and IL-8. In AGS cells, PMA down-regulation of gp-340 was seen in parallel with an up-regulation of the two mature gastric epithelial specific proteins TFF1 (trefoil factor 1) and TFF2, which are implicated as markers of terminal differentiation. Analysis of the distribution of gp-340, together with the TFFs and SP-D in normal lung and gastric mucosa, supported further our in vitro data. We conclude that the differential regulation of gp-340 in the two epithelial cell lines by PMA indicates that gp-340 s involvement in mucosal defence and growth of epithelial cells may vary at different body locations and during different stages of epithelial differentiation.
Interleukin-10 ameliorates the outcome ofStaphylococcus aureusarthritis by promoting bacterial clearance
Authors: GJERTSSON I , HULTGREN O H , TARKOWSKI A 
Published: March 2003

SummaryStaphyllococcus aureus-induced infections often result in high mortality and permanent joint destruction, despite treatment with antibiotics. IL-10 is typically regarded as an anti-inflammatory cytokine because it promotes a T helper cell type 2 response, and subsequently down-regulates cell mediated immune functions. To investigate the role of IL-10 in S. aureus-induced arthritis and sepsis, Balb/c mice, intact or defective with respect to IL-10 gene were intravenously inoculated with bacteria. IL-10–/– mice develop a more frequent and destructive arthritis compared to their congeneic controls. The mechanisms regulating such outcome may be due not only to the anti-inflammatory properties of IL-10 but also, directly or indirectly, to antibacterial features of this molecule. Indeed, inoculation of staphylococci to IL-10–/– mice resulted in higher bacterial load in blood and kidneys compared to congeneic controls. Altogether our data indicate that IL-10 is essential for efficient elimination of bacteria and thereby for protection against septic arthritis.