bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenous glucocorticoids modulate experimental anti-glomerular basement membrane glomerulonephritis
Authors: Leech M , Huang X R , Morand E F , Holdsworth S R 
Published: March 2003

SUMMARY
The influence of endogenous glucocorticoids (GC) on glomerular injury was studied in a rat model of heterologous anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Sprague-Dawley rats underwent adrenalectomy (ADX) or sham-operation 3 days prior to i.v. administration of both nephritogenic (100 μg/g) and subnephritogenic (50 μg/g) doses of sheep anti-rat GBM globulin. Administration of a subnephritogenic dose of anti-GBM globulin resulted in GN in adrenalectomized animals only. Similarly, ADX performed prior to administration of anti-GBM in the nephritogenic dose range resulted in exacerbation of GN compared with sham-operated animals (24 h protein excretion: 190.8 ± 32.8 versus 42.5 ± 2.6 mg/24 h; P &lt; 0.005). In ADX animals receiving subnephritogenic doses of anti-GBM injury was manifested by abnormal proteinuria (62.7 ± 5.8 mg/24 h), accumulation of neutrophils which peaked at 6 h (7.2 ± 1.37 neutrophils per glomerular cross-section (neut/gcs)) and macrophage accumulation in glomeruli at 24 h (6.8 ± 1.2 macrophages/gcs). Sham-adrenalectomized animals given the same dose of anti-GBM globulin developed minimal or no glomerular injury: urinary protein excretion (8.7 ± 1.5 mg/24 h, P &lt; 0.001); neutrophils (0.2 ± 0.04 neutrophils/gcs, P &lt; 0.001); macrophages (1.2 ± 0.5 macrophages/gcs, P &lt; 0.001). The increased cellular recruitment to glomeruli in adrenalectomized animals was associated with glomerular endothelial P-selectin expression. P-selectin expression was not detected in sham-operated rats after anti-GBM injection. Complement deposition in glomeruli was minimal in both groups. Physiologic GC replacement of ADX rats receiving subnephritogenic-dose anti-GBM reversed the observed susceptibility to GN development, with urinary protein excretion (7.8 ± 1.12, P &lt; 0.005) and no detectable P-selectin expression or leucocyte accumulation in glomeruli. These results suggest that endogenous GC modulate heterologous anti-GBM nephritis in rats and that this may be attributable, in part, to regulation of P-selectin expression.
Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice
Authors: Tournoy K G , Depraetere S , Pauwels R A , Leroux-Roels G G 
Published: March 2003

SUMMARYThe innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-β1, a rat monoclonal antibody recognizing the mouse IL-2 receptor β-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-β1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-β1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-β1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-β1. However, these animals died within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-β1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-β1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.
Bacille Calmette–Guérin (BCG)-associated inflammation and fibrosis: modulation by recombinant BCG expressing interferon-gamma (IFN-γ)
Authors: Wangoo A , Brown I N , Marshall B G , Cook H T , Young D B , Shaw R J 
Published: March 2003

SUMMARYImmunization with existing BCG vaccines has failed to confer consistent protection against tuberculosis. One of the ways to improve the efficacy of BCG is by enhancing its ability to induce a type-1 T cell response. However, this approach carries the risk that enhanced immunoreactivity may exacerbate tissue pathology associated with vaccination. The aim of the present study was to determine whether use of a recombinant BCG expressing IFN-γ (BCG-IFN) would result in an alteration in the pattern of inflammation and local tissue fibrosis. A murine intravenous BCG infection model was used in which there was a time- and dose-dependent increase in the weight and number of granulomas in the liver. Infection was associated with increased inflammatory activity in the liver, as shown by the increase in expression of inducible nitric oxide synthase (iNOS) assessed by immunochemistry and by measurement of specific mRNA, and in fibrosis measured by hydroxyproline content of the liver and percentage of granuloma cells staining positively for type 1 procollagen. Infection with BCG-IFN resulted in a reduction in organ weight and bacterial load on day 21 compared with infection with control BCG transformed with vector alone (BCG-plasmid). By day 21, there was also a reduction in iNOS mRNA and iNOS+ cells in granulomas in mice infected with BCG-IFN compared with infection with BCG-plasmid, and a similar reduction in both total number of granulomas and liver hydroxyproline content. These results demonstrate that the granulomas in the areas of mycobacterial infection are active sites of both inflammation and fibrosis, and that the local expression of IFN-γ by the recombinant BCG results in more efficient bacterial clearance which is accompanied by a reduction in tissue pathology.
Variations in cytokine mRNA expression during normal human pregnancy
Authors: Kruse N , Greif M , Moriabadi N F , Marx L , Toyka K V , Rieckmann P 
Published: March 2003

SUMMARYEpidemiological data provide evidence that disease activity of T cell-mediated, organ-specific autoimmune diseases is reduced during pregnancy. Although there are several experimental animal studies on the effect of pregnancy on the immune system, the situation in humans is less clear. We therefore performed a prospective analysis of cytokine mRNA expression in whole blood by a new on-line reverse transcriptase-polymerase chain reaction technique and of serum hormone levels during pregnancy in healthy women. The control group included age-matched non-pregnant healthy women. Quantitativecytokine mRNA expression revealed significantly reduced IL-18, interferon-gamma (IFN-γ), and IL-2 mRNA levels in the first and second trimester in pregnancy compared with non-pregnant women. No difference between groups was detected for tumour necrosis factor-alpha (TNF-α) mRNA. IL-4 and IL-10 mRNA were detected at low levels in only 20% of pregnant women and were reduced to a statistically significant extent in the second and third trimester compared with the control group. Changes in IL-18 mRNA expression correlated inversely with serum values for human choriogonadotropin (HCG) and IL-10 serum levels correlated with increases in serum 17β-oestradiol levels. These data indicate immunomodulatory effects of pregnancy at the cytokine level which may be related to the variations in the clinical course of organ-specific, T cell-mediated autoimmune diseases during pregnancy.
Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients
Authors: Otsuki T , Tomokuni A , Sakaguchi H , Aikoh T , Matsuki T , Isozaki Y , Hyodoh F , Ueki H , Kusaka M , Kita S , Ueki A 
Published: March 2003

SUMMARYDysregulation of apoptosis, particularly in the Fas/Fas ligand (FasL) pathway, is considered to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Recently, a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds FasL and inhibits FasL-induced apoptosis, has been identified. Silicosis is clinically characterized not only by respiratory disorders but by immunological abnormalities. We have found that serum soluble Fas (sFas) levels are elevated in silicosis patients and that sFas message is dominantly expressed in PBMC derived from these patients. This study examined DcR3 gene expression in PBMC derived from patients with silicosis, SLE, or progressive systemic sclerosis (PSS), and compared it with that in healthy volunteers (HV). The relative expression level of the DcR3 gene was examined in PBMC derived from 37 patients with silicosis without clinical symptoms of autoimmune disease, nine patients with SLE, 12 patients with PSS, and 28 HV using the semiquantitative multiplex-reverse transcriptase-polymerase chain reaction (MP-RT-PCR). The correlation between the relative expression level of the DcR3 gene and multiple clinical parameters for respiratory disorders and immunological abnormalities in individuals with silicosis was analysed. The DcR3 gene was significantly over-expressed in cases of silicosis or SLE when compared with HV. In addition, the DcR3 relative expression level was positively correlated with the serum sFas level in silicosis patients. It is unclear, however, whether over-expression of the DcR3 gene in silicosis is caused by chronic silica exposure, merely accompanies the alteration in Fas-related molecules, or precedes the clinical onset of autoimmune abnormalities. It will be necessary to study these patients further, establish an in vitro model of human T cells exposed recurrently to silica compounds, and resolve whether the increase in DcR3 mRNA expression is a cause or consequence of disease.
Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)—possible immunosuppressive role of IFN-α in HIV infection
Authors: Stylianou E , Aukrust P , Bendtzen K , Müller F , Frøland S S 
Published: March 2003

SUMMARYInterferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-α, IFN-γ, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV-infected patients had raised levels of both IP-10 and IFN-α compared with healthy controls (n = 19), with particularly high levels in advanced disease. HAART induced a marked decrease in levels of both IFN-α, neopterin and IP-10, though not to normal concentrations. In contrast, IFN-γ levels were low throughout the study, and not different from controls. While neopterin and IP-10 remained significantly decreased compared with baseline levels throughout the study, IFN-α levels returned to baseline at the end of the study. Persistently high IP-10 and IFN-α levels were associated with immunological treatment failure and even high baseline levels of IFN-α appeared to predict immunological relapse. Furthermore, we found a markedly suppressive effect of exogenously added IFN-α on phytohaemagglutinin-stimulated lymphocyte proliferation in both patients and controls, and this suppressive effect seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-α in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART.
CD4−CD8− T cells bearing invariant Vα24JαQ TCRα-chain are decreased in patients with atopic diseases
Authors: Oishi Y , Sakamoto A , Kurasawa K , Nakajima H , Nakao A , Nakagawa N , Tanabe E , Saito Y , Iwamoto I 
Published: March 2003

SUMMARYAtopic disorders are caused by disregulated activation of T helper 2 (Th2) cells that produce IL-4 and IL-5. Because the presence of IL-4 potently augments the differentiation of naive T cells into Th2 cells, it is important to seek the cell population which provides IL-4 for naive T cells. Recently, a unique subpopulation of T cells, natural killer (NK) T cells, has been shown to produce a large amount of IL-4 upon activation, suggesting their regulatory role in initiation of Th2 cell differentiation. To determine whether NK T cells play a regulatory role in human Th2 cell-mediated atopic diseases, we analysed the frequency of invariant Vα24JαQ CD4−CD8− double-negative (DN) T cells, human NK T cells, in patients with atopic asthma and atopic dermatitis. We also studied cytokine production from Vα24+ Vβ11+ DN T cells, which comprise most of Vα24JαQ DN T cells. We found that the invariant Vα24JαQ DN T cells were greatly diminished in patients with asthma and atopic dermatitis. On the other hand, there was no significant difference in Vα24+ CD4+ T cells possessing invariant Vα24JαQ TCR between healthy subjects and atopic patients. We also found that Vα24+ Vβ11+ DN T cells from healthy subjects predominantly produced interferon-gamma (IFN-γ) but not IL-4 upon activation. These results suggest that NK T cells may not be essential for human atopic disease and that the disappearance of NK T cells, most of which produce IFN-γ, may be involved in the pathogenesis of atopic diseases.
Vaccination of BALB/c mice withLeishmania majoramastigote-specific cysteine proteinase
Authors: Rafati S , Baba A Abraham , Bakhshayesh M , Vafa M 
Published: March 2003

SUMMARYCellular immune mechanisms resulting in interferon-gamma (IFN-γ) production are essential for protection against cutaneous leishmaniasis. Antigens of the intracellular amastigote form of the parasite, found in mammalian hosts, are likely to be good candidates for the induction of T cell response and protection from development of leishmaniasis. We purified a stage-specific antigen from amastigote soluble antigen (A-SLA) of Leishmania major by immunoaffinity chromatography. The purified protein was characterized as a cysteine proteinase with enzymatic activity which is inhibited by E-64, and it was named the amastigote cysteine proteinase (ACP). BALB/c mice were immunized by two intraperitoneal injections, at a month interval, of 5 μg of ACP or A-SLA in Freund’s complete adjuvant (FCA). Animals were challenged 4 weeks later with 106L. major promastigotes and examined 4 months after the last injection. The immunized animals developed significantly smaller or no lesions compared with controls. Spleen cells from immunized mice showed a significant proliferative response and produced a high level of IFN-γ in response to ACP, suggesting the induction of Th1 cells after immunization. These results make 24-kD ACP a possible component for an eventual cocktail vaccine against L. major infection.
Down-regulation of the T cell receptor CD3ζchain in rheumatoid arthritis (RA) and its influence on T cell responsiveness
Authors: Berg L , Rönnelid J , Klareskog L , Bucht A 
Published: March 2003

SUMMARYT cells implicated in chronic inflammatory diseases such as RA respond weakly when stimulated in vitro with mitogen or antigen. The mechanism behind this hyporesponsiveness is unclear, but a depressed expression of the T cell receptor (TCR)-associated CD3ζ chain has been suggested. In the present work we describe a low expression of CD3ζ in synovial fluid (SF) T cells from RA patients compared with peripheral blood (PB) T cells, but no difference in CD3ζ expression between RA and healthy control PB T cells. In vitro studies demonstrated that granulocytes but not SF macrophages are able to down-regulate the expression of CD3ζ. Through stimulation with anti-CD3 antibodies we demonstrated that the TCR-dependent proliferative response was decreased in SF T cells compared with PB T cells. Stimulation with phorbol ester and ionomycin also resulted in a low proliferative response of SF T cells, indicating that both signal transduction through the TCR (stimulation with anti-CD3) and events further downstream in the signalling pathways (stimulation with phorbol ester and ionomycin) are affected. A similar depression of T cell activity was observed when induction of IL-2 and IL-4 was measured. However, SF T cells were not defective in the induction of interferon-gamma (IFN-γ) when stimulated with phorbol myristate acetate (PMA)/ionomycin, in contrast to the diminished IFN-γ response observed after stimulation with anti-CD3. This indicates that the hyporesponsiveness of SF T cells can not be generalized to all T cell functions. The differential response to external stimuli is likely to be of importance for the capacity of SF T cells to influence inflammatory reactions.
Hydroxyurea inhibits the transactivation of the HIV-long-terminal repeat (LTR) promoter
Authors: Calzado M A , Macho A , Lucena C , Muñoz E 
Published: March 2003

SUMMARYHIV-1 gene expression is regulated by the promoter/enhancer located within the U3 region of the proviral 5′ LTR that contains multiple potential cis-acting regulatory sites. Here we describe that the inhibitor of the cellular ribonucleoside reductase, hydroxyurea (HU), inhibited phorbol myristate acetate- or tumour necrosis factor-alpha-induced HIV-1-LTR transactivation in both lymphoid and non-lymphoid cells in a dose-dependent manner within the first 6 h of treatment, with a 50% inhibitory concentration of 0·5 mm. This inhibition was found to be specific for the HIV-1-LTR since transactivation of either an AP-1-dependent promoter or the CD69 gene promoter was not affected by the presence of HU. Moreover, gel-shift assays in 5.1 cells showed that HU prevented the binding of the NF-κB to the κB sites located in the HIV-1-LTR region, but it did not affect the binding of both the AP-1 and the Sp-1 transcription factors. By Western blots and cell cycle analyses we detected that HU induced a rapid dephosphorylation of the pRB, the product of the retinoblastoma tumour suppressor gene, and the cell cycle arrest was evident after 24 h of treatment. Thus, HU inhibits HIV-1 promoter activity by a novel pathway that implies an inhibition of the NF-κB binding to the LTR promoter. The present study suggests that HU may be useful as a potential therapeutic approach for inhibition of HIV-1 replication through different pathways.
Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease
Authors: Louis E , Ribbens C , Godon A , Franchimont D , De Groote D , Hardy N , Boniver J , Belaiche J , Malaise M 
Published: March 2003

SUMMARYInflammatory bowel diseases (IBD) are characterized by a sustained inflammatory cascade that gives rise to the release of mediators capable of degrading and modifying bowel wall structure. Our aims were (i) to measure the production of matrix metalloproteinase-3 (MMP-3), and its tissue inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), by inflamed and uninflamed colonic mucosa in IBD, and (ii) to correlate their production with that of proinflammatory cytokines and the anti-inflammatory cytokine, IL-10. Thirty-eight patients with IBD, including 25 with Crohn’s disease and 13 with ulcerative colitis, were included. Ten controls were also studied. Biopsies were taken from inflamed and uninflamed regions and inflammation was graded both macroscopically and histologically. Organ cultures were performed for 18 h. Tumour necrosis factor-alpha (TNF-α), IL-6, IL-1β, IL-10, MMP-3 and TIMP-1 concentrations were measured using specific immunoassays. The production of both MMP-3 and the TIMP-1 were either undetectable or below the sensitivity of our immunoassay in the vast majority of uninflamed samples either from controls or from those with Crohn’s disease or ulcerative colitis. In inflamed mucosa, the production of these mediators increased significantly both in Crohn’s disease (P &lt; 0·01 and 0·001, respectively) and ulcerative colitis (P &lt; 0·001 and 0·001, respectively). Mediator production in both cases was significantly correlated with the production of proinflammatory cytokines and IL-10, as well as with the degree of macroscopic and microscopic inflammation. Inflamed mucosa of both Crohn’s disease and ulcerative colitis show increased production of both MMP-3 and its tissue inhibitor, which correlates very well with production of IL-1β, IL-6, TNF-α and IL-10.
Prevaccination with SRL172 (heat-killedMycobacterium vaccae) inhibits experimental periodontal disease in Wistar rats
Authors: Breivik T , Rook G A W 
Published: March 2003

SUMMARYPeriodontal disease is a bacterial dental plaque-induced destructive inflammatory condition of the tooth-supporting tissues, which is thought to be mediated by T lymphocytes secreting T helper 2 (Th2) cytokines, resulting in recruitment of high numbers of antibody-producing B lymphocytes/plasma cells as well as polymorphonuclear leucocytes (PMN) secreting tissue-destructive components, such at matrix metalloproteinases and reactive oxygen metabolites into the gingival connective tissues. One treatment strategy may be to down-regulate the Th2 response to those dental plaque microorganisms which induce the destructive inflammatory response. In this study we have examined the effects of a potent down-regulator of Th2 responses on ligature-induced periodontal disease in an experimental rat model. A single s.c. injection into Wistar rats of 0·1 or 1 mg of SRL172, a preparation of heat-killed Mycobacterium vaccae (NCTC 11659), 13 days before application of the ligature, significantly reduced the subsequent destruction of the tooth-supporting tissues, as measured by loss of periodontal attachment fibres (P &lt; 0·001) and bone (P &lt; 0·002). This protective effect occurred not only on the experimental (ligatured) side but also on the control unligatured side. SRL172 has undergone extensive toxicological studies and safety assessments in humans, and it is suggested that it may provide a safe and novel therapeutic approach to periodontal disease.
Follow up of patients with chronic granulomatous disease diagnosed since 1990
Authors: Cale C M , Jones A M , Goldblatt D 
Published: March 2003

SUMMARY
Outcomes for children with chronic granulomatous disease (CGD) have historically been poor, but significant improvements have occurred with the use of effective antibacterial prophylaxis. The present study aimed to document the clinical course of a cohort of children diagnosed with CGD since 1990 in a single centre. Twenty-one patients were identified, with a median age at last assessment of 4 years and 5 months. A third of these children were diagnosed in infancy because of a positive family history. Of the remaining, there was a median delay between the onset of symptoms and diagnosis of 13 months. No invasive or fungal infections were documented after diagnosis, nor were there any deaths in this cohort. A variety of non-infectious complications were noted, which responded well to steroids. As a group, these children were thriving and weight and height distributions fell within the population norm. All patients were receiving antibacterial prophylaxis, 90% with co-trimoxazole, and all but one patient were receiving a prophylactic anti-fungal agent (itraconazole). Both drugs were well tolerated. In conclusion, this cohort of patients, diagnosed in the last decade, tolerated antibacterial and anti-fungal prophylaxis well and on this regimen have a significantly decreased incidence of infection when compared with historical cohorts. Careful follow up of patients who have had aggressive antibacterial and anti-fungal prophylaxis should continue. The data reported on this cohort of patients should inform the debate about the use of more aggressive treatments, such as bone marrow transplantation, in this disease.