bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fucoidan derived fromCladosiphon okamuranus Tokidaameliorates murine chronic colitis through the down-regulation of interleukin-6 production on colonic epithelial cells
Authors: MATSUMOTO S , NAGAOKA M , HARA T , KIMURA-TAKAGI I , MISTUYAMA K , UEYAMA S 
Published: May 2004

SUMMARYOur previous study indicated that the interleukin (IL)-6/STAT-3 signal was up-regulated in inflammatory bowel disease (IBD) in both humans and animal models. We also discovered phosphorylated STAT-3 in the nucleus of the colonic epithelial cells in IBD mice. Intestinal epithelial cells (IEC) have been shown to secrete IL-6. Therefore, the secretion of IL-6 from IEC may be one of the mechanisms of STAT-3 phosphorylation in IEC during the pathogenesis of IBD, and inhibition of IL-6 production by IEC may be beneficial in preventing IBD. We examined the preventative effect of various types of fucoidans on IL-6 production in a lipopolysaccahride (LPS)-stimulated murine colonic epithelial cells line, CMT-93, in vitro. We also determined in vivo the effect of fucoidans on murine chronic colitis induced with dextran sodium sulphate. Among fucoidans, those from Cladosiphon okamuranus Tokida and Kjellmaniella crassifolia inhibited IL-6 production in CMT-93 cells with the down-regulation of NF-κB nuclear translocation. Analysis of the effect of fucoidan on murine colitis in vivo showed that the disease activity index and myeloperoxidase activity decreased in mice fed Cladosiphon fucoidan, but not Fucus fucoidan. Cytokine profiles in colonic lamina propria indicated that the synthesis of interferon (IFN)-γ and IL-6 decreased and that of IL-10 and transforming growth factor (TGF)-β increased in mice fed Cladosiphon fucoidan, compared with mice fed a standard diet or Fucus fucoidan. The levels of IL-6 mRNA in colonic epithelial cells was lower in colitis-induced Balb/c mice fed Cladosiphon fucoidan than those fed a standard diet. Fucoidan improves murine chronic colitis by down-regulating the synthesis of IL-6 in the colonic epithelial cells. Fucoidan derived from C. o. Tokida may be useful as a dietary substance for the patients with inflammatory bowel disease.
Increase in granzyme B+ lymphocytes and soluble granzyme B in bronchoalveolar lavage of allergen challenged patients with atopic asthma
Authors: BRATKE K , BÖTTCHER B , LEEDER K , SCHMIDT S , KÜPPER M , VIRCHOW J C , LUTTMANN W 
Published: May 2004

SUMMARYAsthma has been linked to a chronic, T-cell-mediated bronchial inflammation. Because other T-lymphocyte-mediated, chronic inflammatory disorders have been associated with elevated granzyme B (grB) expression we tested the hypothesis that atopic asthma might be associated with elevated grB levels in the bronchoalveolar compartment. Therefore we performed intracellular grB staining in lymphocytes from bronchoalveolar lavage (BAL) collected 42 h after segmental allergen provocation (SAP) in allergic patients with bronchial asthma. There was a significant increase in CD3+, CD8+, and CD16/56+ lymphocytes expressing grB in BAL 42 h after SAP as compared to saline challenged controls. However, compared to peripheral blood the percentages of these lymphocyte subsets detected as grB+ in BAL remained significantly lower. Measurement of extracellular grB in BAL fluids by a particle immunoassay revealed significantly elevated grB levels in the allergen challenged bronchoalveolar compartment 42 h following SAP in six of the eight patients (range, &lt;1·0–348·1 pg/ml) as compared to saline challenged controls (range, &lt;1·0–70·5 pg/ml). We conclude that total cell numbers of grB+ lymphocyte subsets increase 42 h after SAP in the lower respiratory tract. In addition there is evidence to suggest that grB is released into the airways of asthmatic patients. This suggests a role for grB in the pathophysiological processes following SAP but its definitive role in allergic bronchial asthma needs to be established.
Immunoregulatory defects of Vα24+Vβ11+ NKT cells in development of Wegener's granulomatosis and relapsing polychondritis
Authors: TAKAGI D , IWABUCHI K , IWABUCHI C , NAKAMARU Y , MAGUCHI S , OHWATARI R , FURUTA Y , FUKUDA S , JOYCE S , ONOÉ K 
Published: May 2004

SUMMARYThe frequency of either CD4–8– (double negative; DN) or CD4+ Vα24+Vβ11+ NKT cells, the expression of CD1d and the binding of CD1d-tetramer loaded with α-galactosylceramide (α-GalCer) to NKT cells were analysed in peripheral blood mononuclear cells (PBMCs) of patients with Wegener's granulomatosis (WG), relapsing polychondritis (RP) and healthy subjects (HS). DN and CD4+ Vα24+Vβ11+ NKT cells as well as CD1d-α-GalCer tetramer-positive NKT cells, were significantly decreased in number in both WG and RP patients compared to those from HS. When cytokine profiles were analysed in these PBMCs upon stimulation with phorbol ester and calcium ionophore, CD4+ T cells from patients with WG and RP exhibited a Th1 bias, whereas CD4+ NKT cells from WG patients in remission showed a Th2 bias. These findings suggest that NKT cells (especially CD4+ NKT cells) play a regulatory role in Th1 autoimmunity in patients with WG and RP. The reduction in NKT cell counts appears to be associated with the low responsiveness to α-GalCer. The dysfunction of NKT cells to recognize ligands such as α-GalCer may also contribute to the defects observed in NKT cells from WG and RP patients.
Recognition of nonpeptide antigens by human Vγ9Vδ2 T cells requires contact with cells of human origin
Authors: GREEN A E , LISSINA A , HUTCHINSON S L , HEWITT R E , TEMPLE B , JAMES D , BOULTER J M , PRICE D A , SEWELL A K 
Published: May 2004

SUMMARYIt is becoming apparent that γδ T cells form an important part of the adaptive immune response. However, the ligands recognized by γδ T cell receptors (TCRs) and the exact biological function of the cells that express this receptor remain unclear. Numerous studies have shown that the dominant human peripheral blood subset of γδ T cells, which express a Vγ9Vδ2 TCR, can activate in response to low molecular weight nonpeptidic molecules. Some of these components have been purified from bacteria or parasites. We examined the activation of polyclonal γδ T cell lines, clones with Vγ9Vδ2 and Vγ9Vδ1 TCRs, and γδ T cells directly ex vivo in response to multiple phosphate, alkylamine and aminobisphosphonate (nBP) antigens and purified protein derivative from Mycobacterium tuberculosis (PPD). Vγ9Vδ2 T cells were able to respond to multiple small organic molecules of highly variable structure whereas cells expressing a similar Vγ9 chain paired with a Vδ1 chain failed to recognize these antigens. Thus, the TCR δ chain appears to make an important contribution to the recognition of these antigens. The kinetics of responses to alkylphosphate and alkylamine antigens differ from those of responses to the nBP pamidronate. These different classes of antigen are believed to have differed mechanisms of action. Such differences explain why nBPs can be pulsed onto antigen presenting cells (APCs) and still retain their ability to activate γδ T cells while alkylphosphate and alkylamine antigens cannot. We also demonstrate that a substantial proportion of the cells that produce IFNγ directly ex vivo in response to PPD are γδ T cells and that γδ T cell activation requires contact with cells of human origin.
Differential expression of CTLA-4 among T cell subsets
Authors: JAGO C B , YATES J , OLSEN SARAIVA CÂMARA N , LECHLER R I , LOMBARDI G 
Published: May 2004

SUMMARYCTLA-4 (CD152), the CD28 homologue, is a costimulatory molecule with negative effects on T cell activation. In addition to its role in the termination of activation, CTLA-4 has been implicated in anergy induction and the function of regulatory cells. As an intracellular molecule, it must first relocate to the cell surface and be ligated, in order to inhibit activation. Although some studies have investigated CTLA-4 expression on CD4+ T cells, evidence is lacking regarding the kinetics of expression, and expression on T cell subpopulations. We have investigated CTLA-4 kinetics on human purified peripheral CD4+, naïve, memory, CD4+CD25–, CD4+CD25+ regulatory T cells, and T cell clones. Intracellular stores of CTLA-4 were shown to be very low in naïve T cells, whilst significant amounts were present in memory T cells and T cell clones. Cell surface CTLA-4 expression was then investigated on CD4+CD45RA+ (naïve), CD4+CD45RO+ (memory), CD4+CD25–, and CD4+CD25+ T cells. CD25 and CD45RO are both expressed by regulatory T cells. On naïve and CD4+CD25– T cells, CTLA-4 expression declined after four hours. In contrast, on memory and CD4+CD25+ T cells, high levels of expression were maintained until at least 48 hours. In addition, significant CTLA-4 expression was observed on T cell clones following anergy induction, indicating the potential involvement of CTLA-4 also in this form of tolerance.
Influence of human T lymphotrophic virus type I on diffuse pan-bronchiolitis
Authors: YAMAMOTO M , MATSUYAMA W , OONAKAHARA K , WATANABE M , HIGASHIMOTO I , KAWABATA M , OSAME M , ARIMURA K 
Published: May 2004

SUMMARYHuman T lymphotrophic virus type-I (HTLV-I), a human retrovirus, infects CD4+ lymphocytes and is thought to modify their function and a possible association with pulmonary diseases has also been suggested. However, little is known about the influence of HTLV-I on diffuse pan-bronchiolitis (DPB), a chronic inflammatory lung disease with infiltration of lymphocytes and hyperplasia of the bronchus-associated lymphoid tissue. In this study, 35 DPB patients with and without HTLV-I infection were examined. HTLV-I positive DPB patients were likely to have a larger affected area with lower FEV1. The CD3+/CD25+ lymphocyte percentage was significantly higher in the BALF of HTLV-I positive patients than in negative patients. MIP-1α, IP-10 and levels in BALF were also significantly higher in HTLV-I positive patients than in negative patients. The levels of MCP-1 and IL-8 were not significantly different. In HTLV-I positive patients, the MIP-1α and IP-10 levels showed a significant positive correlation with the percentage of CD3+/CD25 lymphocytes. BALF cells of all HTLV-I positive DPB patients showed expression of p40tax mRNA. We suggest that HTLV-I infection may modify DPB pathogenesis via activation of T cells. We also found that the frequency of ATL development in HTLV-I positive DPB patients was significantly higher than in all HTLV-I positive patients (OR = 8·22, 95% CI = 2·61–25·9, P &lt; 0·01). The levels of TGF-β in patients who developed ATL were significantly lower than in patients who did not develop ATL. Sensitivity and specificity were 80% and 85·7%, respectively (cut-off = 20 pg/ml). We also propose that these features should be taken into consideration in the treatment of DPB in HTLV-I infected individuals.
Effects of commonly used immunosuppressants on graft-derived fibroblasts
Authors: JOHNSSON C , GERDIN B , TUFVESON G 
Published: May 2004

SUMMARYIn acute rejection of transplanted organs intragraft fibroblasts increase their production of hyaluronan. Hyaluronan has strong water binding capacity and an increased tissue content of hyaluronan thus contributes to the development of interstitial oedema. The present study examined the effects of commonly used immunosuppressants (prednisolone, cyclosporin, tacrolimus, mycophenolic acid and sirolimus) on fibroblast proliferation, hyaluronan production and cell surface receptor expression. Fibroblasts isolated from rejecting tissue and from normal, non-transplanted tissue were studied in parallel. All substances investigated, except tacrolimus, were found to affect fibroblasts in one way or another. The most striking effect was the almost total inhibition of fibroblast proliferation in the presence of mycophenolic acid. Cyclosporin reduced the proliferation by about 50% and prednisolone had an inhibiting effect on hyaluronan production (50% reduction). These effects were observed on fibroblasts isolated from rat cardiac allografts undergoing rejection as well as on fibroblasts obtained from normal heart tissue. In contrast, sirolimus was found to stimulate the proliferation of fibroblasts from rejecting tissue (100% increase), but not that of normal fibroblasts. The majority of the fibroblasts expressed the hyaluronan receptor CD44, with a more intense expression in cultures of fibroblasts derived at rejection. None of the immunosuppressants affected the staining pattern (number of positive cells or intensity). The inhibitory effects of prednisolone, cyclosporin and mycophenolic acid on fibroblasts may contribute to the overall beneficial effects of these drugs when used for prevention or treatment of rejection.
Differential gene expression in mononuclear phagocytes infected with pathogenic and non-pathogenic mycobacteria
Authors: MCGARVEY J A , WAGNER D , BERMUDEZ L E 
Published: May 2004

SUMMARYThe pathogenic mycobacteria are an insidious group of bacterial pathogens that cause the deaths of millions of people every year. One of the reasons these pathogens are so successful is that they are able to invade and replicate within host macrophages, one of the first lines of defence against intruding pathogens. In contrast, non-pathogenic mycobacteria, such as Mycobacterium smegmatis are killed rapidly by macrophages. In order to understand better the series of events that allow pathogenic mycobacteria to survive and replicate within macrophages, while the non-pathogenic mycobacteria are killed rapidly, we inoculated the human monocytic cell line U937 with pathogenic (M. tuberculosis and M. avium) and non-pathogenic (M. smegmatis) mycobacteria and monitored the expression of over 3500 genes at 4, 12 and 24 h post-inoculation using a commercially available gene array system. We observed multiple differences in the gene expression patterns of monocytes infected with pathogenic and non-pathogenic mycobacteria including genes involved in cytokine, lymphokine and chemokine production, adhesion, apoptosis, signal transduction, transcription, protein cleavage, actin polymerization and growth. We also observed differences in gene expression profiles in monocytes infected with M. tuberculosis or M. avium, indicating that there are differences in the host pathogen interactions of mononuclear phagocytes infected with different pathogenic mycobacterial species. These results increase the understanding of the mechanisms used by pathogenic mycobacteria to cause disease, the host response to these organisms, and provide new insights for antimycobacterial intervention strategies.
Ectopic expression of CCL19 impairs alloimmune response in mice
Authors: Krautwald Stefan , Ziegler Ekkehard , Förster Reinhold , Ohl Lars , Amann Kerstin , Kunzendorf Ulrich 
Published: May 2004

SummaryInitiation of an antitumour immune response is characterized by a complex process of chemokine‐mediated cell migration and cell–cell interactions. Overexpression of chemokine CCL19 in tumour cells has been shown to result in accelerated tumour rejection under certain experimental conditions, suggesting a novel approach in the therapy of neoplastic malignancies. To investigate CCL19‐mediated modulations of cellular immune responses in vivo, we generated a chimeric CCL19‐immunoglobulin G2b (IgG2b) Fc fusion protein, which binds to the chemokine receptor CCR7 comparable to native CCL19. CCL19‐IgG2b possesses a long‐lasting potent chemotactic activity as a result of the extended half‐life of Fc fusion proteins. Stable overexpression of CCL19‐IgG2b in BALB/c‐derived J558L tumour cells fails to support tumour cell rejection following transplantation in syngeneic mice. Moreover, overexpression of CCL19‐IgG2b hinders tumour rejection in allogeneic C57BL/6 mice. This phenomenon was accompanied by a six‐fold increase of dendritic cells (DCs) isolated from CCL19‐IgG2b‐secreting tumours when compared to the number of DCs isolated from control parental J558L tumours. While mice bearing the allogeneic parental tumour showed an intense hypercellularity in the draining lymph nodes, no such response could be observed in the draining lymph nodes of mice carrying the CCL19‐IgG2b‐secreting tumour. We could demonstrate that overexpression of CCL19‐IgG2b in tumour cells retains antigen‐presenting cells in the tumour mass and prevents DCs from migrating into draining lymph nodes to present antigens and to activate T cells, resulting in an impaired immune response against the tumour.
Aberration of CCR7+ CD8+ memory T cells from patients with systemic lupus erythematosus: an inducer of T helper type 2 bias of CD4+ T cells
Authors: Sen Yang , Chunsong Hu , Baojun Huang , Linjie Zhang , Qun Li , San Jiang , Qiuping Zhang , Junyan Liu , Zhang Xuejun , Jinquan Tan 
Published: May 2004

SummaryChemokine receptors are important in the entry of leucocytes into the inflammatory sites of systemic lupus erythematosus (SLE). CCR7+ and CCR7– memory T cells exert different functions in homing, cytokine production and cytotoxicity. To determine whether differential expression and functions of the CCR7 occur in SLE patients, we examined CCR3, CCR4, CCR5, CCR7 and CCR9 on CD4+ and CD8+ T cells from normal and SLE subjects. Flow cytometry, real‐time quantitative reverse transcription polymerase chain reactions and Northern blotting were used to detect the expression of chemokine receptors and cytokines; a chemotaxis assay was used to detect their functions. CD4+ T‐cell stimulation with syngeneic CCR7+ CD8+ CD45RO+ T cells and dendritic cells (including transwell chambers) was used to induce cytokine expression. We demonstrated that CCR7 was selectively, frequently and functionally expressed on CD8+ (94·8%) but not on CD4+ (16·1%) T cells from patients with active SLE, whereas this phenomenon was not seen in normal subjects and in those whose SLE was inactive. CCR7+ CD8+ CD45RO+ memory T cells from patients with active SLE, themselves T helper type 2 (Th2) biased, were inducers of Th2 bias in CD4+ T cells in a cell–cell contact manner in vitro, meanwhile, the cells from both normal subjects and those whose SLE was inactive drove CD4+ T cells into a regulatory T‐cell‐derived cytokine pattern. Our findings might provide new clues to understanding the functions of CCR7+ CD8+ CD45RO+‘central’ memory T cells in autoimmue diseases (such as SLE). We suggest that in the case of active SLE, CCR7+ central memory T cells were able to enter peripheral blood and inflammatory sites from secondary lymphoid organs, were continuously expressing CCR7, and interacted with dendritic cells and functioned as CCR7–‘effector’ memory T cells, which were described in normal humans.
Irradiation up‐regulates CD80 expression through two different mechanisms in spleen B cells, B lymphoma cells, and dendritic cells
Authors: Torihata Hideko , Ishikawa Fumio , Okada Yayoi , Tanaka Yuriko , Uchida Tetsuya , Suguro Toru , Kakiuchi Terutaka 
Published: May 2004

SummaryWe have previously demonstrated irradiation‐induced up‐regulation of CD80 expression in A20‐HL B lymphoma cells by inducing expression of tumour necrosis factor‐α (TNF‐α) and CD154. In the present study, we investigated whether irradiation also up‐regulates CD80 expression in mouse spleen B cells. Because freshly prepared spleen B cells are highly sensitive to irradiation, we employed spleen B cells stimulated with lipopolysaccharide (LPS‐B cells). X‐irradiation (8 Gy) followed by incubation (9–12 hr) highly and selectively up‐regulated CD80 expression in LPS‐B cells, whereas the same treatment slightly increased expression of CD54 and did not affect expression of CD86, major histocompatibility complex class II, CD11a or surface immunoglobulin M. The irradiation‐induced up‐regulation of CD80 expression resulted in enhanced APC function of LPS‐B cells. Up‐regulation of CD80 expression on LPS‐B cells was accompanied by an increase in CD80 mRNA accumulation and nuclear factor (NF)‐κB activation. Activation of NF‐κB was shown to be critical for up‐regulation of CD80 expression as pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF‐κB, severely decreased the observed up‐regulation. X‐irradiation of LPS‐B cells induced expression of TNF‐α but not CD154. However, anti‐TNF‐α monoclonal antibody (mAb) with anti‐CD154 mAb did not inhibit X‐irradiation‐induced up‐regulation of CD80 expression in LPS‐B cells, whereas these mAbs almost completely inhibited this up‐regulation in A20‐HL cells and bone marrow‐derived dendritic cells (DCs). In contrast, a thiol antioxidant, N‐acetyl‐l‐cysteine, completely blocked X‐irradiation‐induced up‐regulation of CD80 expression in LPS‐B cells, but not in A20‐HL cells or in DCs. Based on these findings, we concluded that X‐irradiation up‐regulates CD80 expression not only in A20‐HL cells and DCs but also in LPS‐B cells, and that this up‐regulation in LPS‐B cells via NF‐κB activation is dependent on the generation of reactive oxygen species, while that in A20‐HL cells and DCs is not.
Selective killing of B‐cell hybridomas targeting proteinase 3, Wegener's autoantigen
Authors: Reiners Katrin S. , Hansen Hinrich P. , Krüssmann Anne , Schön Gisela , Csernok Elena , Gross Wolfgang L. , Engert Andreas , Von Strandmann Elke Pogge 
Published: May 2004

SummaryWegener's granulomatosis (WG) is a rare disease characterized by granulomatous lesions, small vessel vasculitis and the presence of anti‐neutrophil cytoplasmic autoantibodies (C‐ANCAs) in the sera of affected patients. Their main target antigen is proteinase 3 (PR3), a neutrophil and monocyte‐derived neutral serine protease. Since the standard treatment of this severe autoimmune disease, with cyclophosphamide and corticosteroids, is associated with potential side‐effects, the development of a more specific immunotherapeutic agent is warranted. The key role of ANCA in the pathogenesis of vasculitis and the effectiveness of anti‐CD20 antibodies in patients with refractory WG points towards the importance of B cells in WG. We thus evaluated a new approach to selectively eliminate PR3‐specific autoreactive B cells by targeting the B‐cell receptor. For this purpose we used a bifunctional recombinant fusion protein consisting of the antigen PR3 and a toxin. The cytotoxic component of this novel fusion protein was the ribonuclease angiogenin, a human toxin with low immunogenicity. The toxin was stabilized by exchanging the catalytically relevant histidine in position 44 with glutamine to eliminate the autoproteolytic activity. PR3H44Q was fused either to the N terminus or to the C terminus of angiogenin. The recombinant proteins were expressed in 293T cells. Binding assays demonstrated the appropriate size and recognition by anti‐PR3 antibodies. Using TUNEL technology, we demonstrated that these autoantigen toxins kill proteinase 3‐specific B‐cell hybridomas selectively by inducing apoptosis. The data indicate that autoantigen‐toxins are promising tools in the treatment or co‐treatment of autoimmune diseases in which the antigen is known.