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G Hartmann

Publications and source records attributed to G Hartmann.

At least 37 records · Page 2Linked to original sources
PubMed2001

Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.

Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha, IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

Animals↗
PubMed2001

Adenosine kinase inhibitor GP515 improves experimental colitis in mice.

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.

Adenosine Kinase↗
PubMed2001

CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens.

Multiple factors, including expression of costimulatory molecules, antigen-presenting molecules, and target antigens, likely impact the efficacy of antibody therapy and other approaches to the immunotherapy of B cell malignancy. Unmethylated CpG-dinucleotides in select base contexts ("CpG motifs") that resemble sequences found in bacterial DNA are potent immunostimulatory agents capable of inducing a complex immune response, including a strong B cell stimulus. We examined the effect of a potent human CpG oligonucleotide (CpG ODN 2006) on different types of primary human malignant B cells and reactive follicular hyperplasia. CpG oligodeoxynucleotide (CpG ODN), but not control (non-CpG ODN), increased the expression of costimulatory molecules (CD40, CD80, CD86, CD54) on malignant B cells without altering the phenotype of B cells obtained from reactive follicular hyperplasia. CpG ODN also enhanced expression of class I and class II MHC in most samples. CD20 expression was increased in response to CpG ODN, most notably in B-CLL and marginal zone lymphoma. An inverse correlation was found between baseline expression of CD20 and CD40 and their expression after exposure to CpG ODN, thus the most significant increase in expression of these molecules was found in those samples that had the lowest baseline levels. In conclusion, CpG ODN can lead to increasing expression of molecules involved in costimulation, antigen presentation, and as targets for antibody-based therapy and deserve further evaluation as potential immunotherapeutic agents for B cell malignancy.

Antigen Presentation↗
PubMed2000

Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo.

Dendritic cells (DC) manipulated ex vivo can induce tumor immunity in experimental murine tumor models. To improve DC-based tumor vaccination, we studied whether DC maturation affects the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4 alone or by further addition of TNF-alpha or a cytidine-phosphate-guanosine (CpG)-containing oligonucleotide (ODN-1826), which mimics the immunostimulatory effect of bacterial DNA. Flow cytometric analysis of costimulatory molecules and MHC class II showed that DC maturation was stimulated most by ODN-1826, whereas TNF-alpha had an intermediate effect. The extent of maturation correlated with the secretion of IL-12 and the induction of alloreactive T cell proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated DC cocultured with irradiated tumor cells also induced prophylactic protection most effectively and were therapeutically effective when administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC maturation may represent an efficient means to improve clinical tumor vaccination.

Adjuvants, Immunologic↗
PubMed2000

Nontoxigenic sorbitol-fermenting Escherichia coli O157:H- associated with a family outbreak of diarrhoea.

A recent study from Germany reported the isolation of E. coli O157:H7/H- from patients with non-bloody diarrhoea and hemolytic uremic syndrome, questioning the role of Shiga toxin as the main trait of virulence for human disease. We isolated 6 sorbitol-fermenting E. coli O157:H- strains that do not contain Shiga toxin genes. The isolates originated from an outbreak (3 patients, 3 asymptomatic contacts) of non-bloody diarrhoea affecting two families sharing one household. Two children (age 10 months and 2 years) suffered severe diarrhoea over 30 and 10 days, respectively. Their uncle had moderate diarrhoea for 2 weeks. In contrast to the other isolates, the uncle's strain (EH109) did not harbour a chromosomal eae gene encoding gamma-intimin nor the plasmid gene E-hly; it also showed a PFGE pattern that was different from the unique pattern of the other isolates. Employing PFGE, phage typing, and P-gene typing, five of the six stx negative isolates were indistinguishable from the stx 2 positive "Bavarian outbreak strain". The only human serum tested, obtained from one asymptomatic contact, contained antibodies to the O157 lipopolysaccharide antigen. Our finding of five stx negative sorbitol-fermenting E. coli O157:H- isolates (harbouring eae and E-hly) associated with an outbreak of non-bloody diarrhoea supports the hypothesis that Stx production is not obligatory for the pathogenicity of E. coli O157 for humans.

Adult↗
PubMed2000

Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo.

Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides within specific sequence contexts (CpG motifs) are detected, like bacterial or viral DNA, as a danger signal by the vertebrate immune system. CpG ODN synthesized with a nuclease-resistant phosphorothioate backbone have been shown to be potent Th1-directed adjuvants in mice, but these motifs have been relatively inactive on primate leukocytes in vitro. Moreover, in vitro assays that predict in vivo adjuvant activity for primates have not been reported. In the present study we tested a panel of CpG ODN for their in vitro and in vivo immune effects in mice and identified in vitro activation of B and NK cells as excellent predictors of in vivo adjuvant activity. Therefore, we tested >250 phosphorothioate ODN for their capacity to stimulate proliferation and CD86 expression of human B cells and to induce lytic activity and CD69 expression of human NK cells. These studies revealed that the sequence, number, and spacing of individual CpG motifs contribute to the immunostimulatory activity of a CpG phosphorothioate ODN. An ODN with a TpC dinucleotide at the 5' end followed by three 6 mer CpG motifs (5'-GTCGTT-3') separated by TpT dinucleotides consistently showed the highest activity for human, chimpanzee, and rhesus monkey leukocytes. Chimpanzees or monkeys vaccinated once against hepatitis B with this CpG ODN adjuvant developed 15 times higher anti-hepatitis B Ab titers than those receiving vaccine alone. In conclusion, we report an optimal human CpG motif for phosphorothioate ODN that is a candidate human vaccine adjuvant.

Adjuvants, Immunologic↗
PubMed2000

Mechanism and function of a newly identified CpG DNA motif in human primary B cells.

The vertebrate immune system recognizes bacterial DNA based on the presence of unmethylated CpG-dinucleotides in particular base contexts ("CpG motifs"). In contrast to mice, knowledge about CpG-mediated effects on human B cells is poor. In the present study we identify and determine an optimal human CpG motif. A phosphodiester oligonucleotide containing this motif strongly stimulated CD86, CD40, CD54, and MHC class II expression, IL-6 synthesis, and proliferation of primary human B cells. These effects required internalization of the oligonucleotide and endosomal maturation. The molecular mechanism of action of this CpG motif was associated with the sustained induction of the NF-kappaB p50/p65 heterodimer and of the transcription-factor complex AP-1. Transcription-factor activation by CpG DNA was preceded by increased phosphorylation of the stress kinases c-Jun N-terminal kinase and p38, and of activating transcription factor-2. In contrast to CpG, signaling through the B cell receptor led to activation of extracellular receptor kinase and to phosphorylation of a different isoform of c-Jun N-terminal kinase. These studies define the structure of a highly active human CpG motif and characterize its molecular mechanism of action in primary human B cells.

Activating Transcription Factor 2↗
PubMed2000

High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein.

Hypoxic pulmonary vasoconstriction is associated with but may not be sufficient for the development of high-altitude pulmonary oedema (HAPO). Hypoxia is known to induce an inflammatory response in immune cells and endothelial cells. It has been speculated that hypoxia-induced inflammatory cytokines at high altitude may contribute to the development of HAPO by causing capillary leakage in the lung. We were interested if such an inflammatory response, possibly involved in a later development of HAPO, is detectable at high altitude in individuals without HAPO. We examined the plasma levels of interleukin 6 (IL-6), interleukin 1 receptor antagonist (IL-1ra) and C-reactive protein (CRP) in two independent studies: study A, Jungfraujoch, Switzerland, three overnight stays at 3458 m, n=12; study B: Capanna Regina Margherita, Italy, 3 overnight stays at 3647 m and one overnight stay at 4559 m, n=10. In both studies, probands showed symptoms of acute mountain sickness but no signs of HAPO. At the Jungfraujoch, IL-6 increased from 0.1+/-0.03 pg/ml to 2. 0+/-0.5 pg/ml (day 2, P=0.03), IL-1ra from 101+/-21 to 284+/-73 pg/ml (day 2, P=0.01), and CRP from 1.0+/-0.4 to 5.8+/-1.5 micrograms/ml (day 4, P=0.01). At the Capanna Margherita, IL-6 increased from 0. 5+/-0.2 pg/ml to 2.0+/-0.8 pg/ml (P=0.02), IL-1ra from 118+/-25 to 213+/-28 pg/ml (P=0.02), and CRP from 0.4+/-0.03 to 3.5+/-1.1 micrograms/ml (P=0.03). IL-8 was below the detection limit of the ELISA (<25 pg/ml) in both studies. The increase of IL-6 and IL-1ra in response to high altitude was delayed and preceded the increase of CRP. We conclude that: (1) circulating IL-6, IL-1ra and CRP are upregulated in response to hypobaric hypoxic conditions at high altitude, and (2) the moderate systemic increase of these inflammatory markers may reflect considerable local inflammation. The existence and the kinetics of high altitude-induced cytokines found in this study support the hypothesis that inflammation is involved in the development of HAPO.

Adult↗
PubMed2000

Anabolic steroids impair the exercise-induced growth of the cardiac capillary bed.

BACKGROUND: Concomitant application of anabolic-androgenic steroids and physical exercise can induce cardiac hypertrophy. These experiments investigate the still unknown response of the cardiac myocytes and capillaries to the combined influence of various anabolic steroids and muscular exercise. METHODS: Female SPF-NMRI mice were divided into the following groups: a) sedentary control, b) exercise (treadmill running); c) sedentary receiving Dianabol; d) exercise + Dianabol; e) exercise + Oral-Turinabol. After 3 and 6 weeks the left ventricular papillary muscles were studied morphometrically. Evaluated variables: minimal myocyte diameter, number of capillaries around a single myocyte, capillary density and intercapillary distance. RESULTS: Only the anabolic steroids + exercise groups showed a mild myocyte hypertrophy. In contrast, only exercise alone caused a significant increase of the capillary density after both experimental periods; e.g. capillary density after 6 weeks (capillaries/mm2, mean values +/- standard deviation, p < 0.05): control (4,272 +/- 287), exercise (5411 +/- 755), dianabol (4,004 +/- 333), dianabol + exercise (4,076 +/- 403), oral-turinabol + exercise (4,053 +/- 306). Moreover, unlike all other regimens, only exercise alone shortened the intercapillary distance. Finally, exercise without drugs induced the greatest increase in the number of capillaries around a single myocyte. CONCLUSIONS: Anabolic steroids combined with exercise: 1) induce mild hypertrophy of the cardiac myocytes, 2) impair the cardiac microvascular adaptation to physical conditioning. The microvascular impairment may cause a detrimental alteration of the myocardial oxygen supply, especially during muscular exercise.

Anabolic Agents↗
PubMed2000

Testosterone-propionate impairs the response of the cardiac capillary bed to exercise.

OBJECTIVE: Experimental application of anabolic-androgenic steroids and exercise training induce cardiac hypertrophy. This study quantifies for the first time, on microscopical level, the adaptation of the cardiac capillaries and myocytes to the concomitant application of testosterone-propionate and exercise training. METHODS: Female SPF-NMRI mice were studied over 3 and 6 wk. Experimental groups: (i) sedentary control (C); (ii) exercise (treadmill running, E); (iii) testosterone-propionate (TP); and (iv) testosterone-propionate+exercise (TPE). Morphometric parameters: 1) papillary muscles: capillary density, intercapillary distance, number of capillaries around a myocyte, and minimal myocyte diameter; and 2) left ventricular wall: capillary density and intercapillary distance. RESULTS: Papillary muscle: A striking suppression of the exercise-induced improvement in capillary supply occurs in the testosterone-propionate+exercise groups over 3 and 6 wk. Exercise without drugs increases significantly (P < 0.05) the capillary density, shortens significantly (P < 0.05) the intercapillary distance, whereas it increases the number of capillaries around a myocyte. These alterations are not observed in the testosterone-propionate treated sedentary animals; e.g., capillary density after 6 wk (mean values +/- standard deviation, capillaries x mm(-2)): C: 4272 +/- 287, E: 5411 +/- 758, TP: 4221 +/- 364, and TPE: 3997 +/- 397. Moreover, only in the testosterone-propionate+exercise groups occurs a mild myocyte hypertrophy after both time periods: there is a trend toward hypertrophy (P < 0.1) in comparison with the C groups and a significant hypertrophy (P < 0.05) in comparison with the E groups. CONCLUSIONS: Testosterone-propionate profoundly inhibits the exercise-induced augmented capillarization, whereas (under training conditions) it leads to a mild myocyte hypertrophy. The microvascular impairment could trigger an imbalance between the myocardial oxygen supply and demand, especially during physical exercise.

Animals↗
PubMed2000

Serum protein 90K/Mac-2BP is an independent predictor of disease severity during hepatitis C virus infection.

The serum protein designated 90K/Mac-2BP has been found at elevated concentrations in the sera of patients with various types of cancer and viral infections. The importance of the 90K/Mac-2BP serum concentrations in predicting the response towards interferon-alpha treatment for hepatitis C virus (HCV) infection prompted us to utilize a new ELISA for soluble human 90K/Mac-2BP to monitor the serum concentrations of this protein in our HCV-positive patients. Seventy HCV-PCR and anti-HCV antibody positive patients were analyzed for their serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, cholinesterase, HCV-viral load, viral subtypes, and 90K/Mac-2BP. On correlation of age and 90K/Mac-2BP levels, we found an apparent correlation that was proved rather to be a strong dependence of 90K/Mac-2BP concentrations on disease severity/duration, which increases with age. Multiple correlation analysis demonstrated the independent nature of 90K/Mac-2BP concentrations, underscoring the potential high utility of this new marker. Our data corroborate the potential of the scavenger receptor family protein 90K/Mac-2BP as an independent predictor of disease severity during HCV infection.

Adolescent↗
PubMed2000

Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice.

The specific type IV phosphodiesterase inhibitor rolipram is a potent suppressor of tumor necrosis factor-alpha (TNF) synthesis. We examined the efficacy of rolipram for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulfate sodium in their drinking water continuously for up to 11 days. Colitis was quantified by a clinical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histologic score (range from 0 to 6); and by detecting TNF concentration in colonic tissue by enzyme-linked immunosorbent assay. In a first protocol, rolipram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfate sodium. Rolipram reduced the clinical activity of colitis (score 1.1 +/- 0.3) compared with mice that did not receive rolipram (2.4 +/- 0.4; P =.041). Rolipram also partially reversed the reduction of colon length (without rolipram, 12.4 +/- 0. 3 cm; with rolipram, 15.4 +/- 0.7 cm; P =.004) and improved the histologic score (1.5 +/- 0.6 in rolipram-treated mice versus 4.6 +/- 0.5; P =.020). Rolipram suppressed colonic tissue TNF concentrations. The beneficial effect of rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and rolipram was administered from day 8 through day 15. These three series of experiments on a total of 153 mice documented the efficacy of rolipram in both the prevention and treatment of experimental colitis.

Animals↗
PubMed2000

Suppression of TNF-alpha production in human mononuclear cells by an adenosine kinase inhibitor.

Adenosine exerts potent anti-inflammatory activities through inhibition of cytokine synthesis by activated monocytes. Adenosine is rapidly phosphorylated intracellularly by adenosine kinase. GP515, an adenosine kinase inhibitor, prevents the phosphorylation of adenosine to AMP and thereby locally enhances the adenosine concentration. GP515 has exhibited significant anti-inflammatory effects in several murine models of inflammation. In this study we investigated the effect of GP515 alone and in combination with exogenous adenosine or with rolipram, a phosphodiesterase inhibitor, on tumor necrosis factor alpha (TNF-alpha) synthesis in human peripheral blood mononuclear cells (PBMC) or whole blood. Lipopolysaccharide (LPS; 10 ng/mL)-stimulated PBMC were incubated in the absence or presence of these substances. GP515 alone showed a dose-dependent suppression of TNF-alpha production with an IC50 of 80 microM. The TNF-alpha-inhibiting effects of adenosine and GP515 were reversed in the presence of the cAMP antagonist (Rp)-cAMPS, supporting the hypothesis of a cAMP-mediated pathway. Combinations of GP515 with either adenosine or rolipram led to an additive inhibition of TNF-alpha synthesis. These experiments are the first to demonstrate efficacy of an adenosine kinase inhibitor in TNF-alpha suppression in cells of human origin. The findings form a basis to investigate these strategies in animal models of TNF-alpha-mediated chronic inflammatory diseases.

Adenosine↗
PubMed2000

[Clinical aspects, course and extrahepatic manifestations of hepatitis C].

Hepatitis C virus infection occasionally causes acute icteric hepatitis. However, primary infection is usually asymptomatic. Viral clearance occurs only in 20%; most patients develop a chronic hepatitis, which tends to be hardly symptomatic for many years. The risk of progression to cirrhosis, hepatocellular carcinoma and end-stage liver disease is associated with the severity of histopathological changes, and is increased by additional factors, such as excessive alcohol intake or coinfection with hepatitis B virus and HIV. Immunologically mediated extrahepatic manifestations of hepatitis C, in particular essential mixed cryoglobulinemia, can often be observed. Occasionally, they lead to fatal complications.

AIDS-Related Opportunistic Infections↗
PubMed2000

Physicochemical analysis of purified diphtheria toxoids: is toxoided then purified the same as purified then toxoided?

Diphtheria toxin can be converted into a highly immunogenic and irreversibly detoxified vaccine either using the conventional process in which the crude toxin is formalinised and subsequently purified (DTxd(conv)) or by detoxification of the highly purified toxin (DTxd(new)). In this study, both DTxd(new) and DTxd(conv) were evaluated by use of physico-chemical methods. For some methods, results were also compared to those obtained for cross-reacting material (CRM197), which is a non-toxic mutant of diphtheria toxin. DTxd(new) was assayed to have a specific purity of at least 2300 LF/mg protein N, thereby exceeding Pharm. Eur. requirements by up to 35%. Superior purity of DTxd(new) could also be demonstrated by size exclusion HPLC experiments and by amino acid composition studies. Far-UV circular dichroism spectroscopy revealed that the secondary structure of DTxd(new) almost resembled that of CRM197, suggesting only minor molecular changes during detoxification. This study worked out differences between purified diphtheria toxoids. Physico-chemical means revealed the advantages of DTxd(new) being the purer and more defined product, thus making it highly efficient for its use as a vaccine carrier as well as a component of vaccine combinations.

Amino Acids↗
PubMed1999

CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells.

DNA molecules containing unmethylated CpG-dinucleotides in particular base contexts ("CpG motifs") are excellent adjuvants in rodents, but their effects on human cells have been less clear. Dendritic cells (DCs) form the link between the innate and the acquired immune system and may influence the balance between T helper 1 (Th1) and Th2 immune responses. We evaluated the effects of CpG oligodeoxynucleotides alone or in combination with granulocyte-macrophage colony-stimulating factor (GMCSF) on different classes of purified human DCs. For primary dendritic precursor cells isolated from human blood, CpG oligonucleotides alone were superior to GMCSF in promoting survival and maturation (CD83 expression) as well as expression of class II MHC and the costimulatory molecules CD40, CD54, and CD86 of DCs. Both CD4-positive and CD4-negative peripheral blood dendritic precursor cells responded to CpG DNA which synergized with GMCSF but these DCs showed little response to lipopolysaccharide (LPS). In contrast, monocyte-derived DCs did not respond to CpG, but they were highly sensitive to LPS, suggesting an inverse correlation between CpG and LPS sensitivity in different subsets of DCs. Compared with GMCSF, CpG-treated peripheral blood DCs showed enhanced functional activity in the mixed lymphocyte reaction and induced T cells to secrete increased levels of Th1 cytokines. These findings demonstrate the ability of specific CpG motifs to strongly activate certain subsets of human DCs to promote Th1-like immune responses, and support the use of CpG DNA-based trials for immunotherapy against cancer, allergy, and infectious diseases.

Adjuvants, Immunologic↗