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E Stüber

Publications and source records attributed to E Stüber.

29 records · Page 2Linked to original sources
PubMed1998

Infected bile-induced acute pancreatitis in rabbits. The role of bacteria.

CONCLUSIONS: Bacteria species commonly found in bile of patients with choledocholithiasis render human bile toxic to the pancreas. The severity of infected bile-induced acute pancreatitis depends on the bacterial species. Infected bile-induced acute pancreatitis turns into a sterile inflammation within 10 d. BACKGROUND: Flow of bile into the pancreatic duct was proposed to cause some forms of gallstone pancreatitis. The development of bile-induced acute pancreatitis at physiologic ductal pressure is known to depend on the bacterial infection of bile. In this study, we investigated the effect of a variety of bacteria species commonly found in bile of patients with choledocholithiasis upon the pancreatic toxicity of human bile. The time-course of pancreatic infection in infected bile-induced acute pancreatitis was also analyzed. METHODS: In rabbits, the pancreatic duct was kept obstructed throughout the experiment. After 24 h, 50 microL of pancreatic juice was obtained from the congested pancreatic duct and replaced with the same quantity of infected human bile. Bile contained bacteria (10(7) microorganisms/microL) of species frequently found in choledochal secretions of patients with gallstone disease. Effects on pancreatic morphology were studied after 48 h. In another experiment, the number of Escherichia coli/mg of pancreatic tissue was determined in a time sequence study following exposure of the rabbit pancreatic duct to 50 microL E. coli-infected bile (10(7) microorganisms/mL) and temporary (12 h) or permanent duct obstruction. RESULTS: Sterile bile was not harmful to the pancreas. Infected bile caused an interstitial-edematous pancreatitis with occasional acinar necrosis. The severity of acute pancreatitis depended on the bacterial species. Following pancreatic duct exposure to E. coli-infected bile, there was complete clearance of the bacteria from the gland with a concomitant interstitial leukocyte infiltration within a period of 2-10 d.

Acute Disease↗
PubMed1998

Involvement of OX40-OX40L interactions in the intestinal manifestations of the murine acute graft-versus-host disease.

BACKGROUND & AIMS: The intestinal histology of murine semiallogeneic graft-versus-host (GVH) disease is characterized by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. Mechanisms of T cell-mediated changes of the mucosal architecture were investigated. METHODS: The rate of cellular apoptosis and proliferation, changes in the composition of extracellular matrix (ECM), and the role of OX40-OX40L interactions in the pathogenesis of villous atrophy and crypt hyperplasia were examined. RESULTS: The rate of apoptosis and the number of proliferating cells were significantly increased in GVH animals compared with control animals. In addition, expression of tenascin, an ECM component, was down-regulated in GVH animals. Inhibition of OX40-OX40L interactions in GVH animals by administration of an OX40-Ig fusion protein completely prevented the development of crypt hyperplasia and villous atrophy in GVH animals. Tenascin expression was up-regulated in OX40-Ig-treated mice compared with GVH animals, suggesting an important function of this ECM component in mucosal repair. CONCLUSIONS: The OX40-OX40L interaction is crucial in the pathogenesis of GVH, a T cell-mediated intestinal disease. The data suggest that the ECM component tenascin is probably relevant for the regeneration and maintenance of intestinal tissue architecture.

Acute Disease↗
PubMed1996

Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses.

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.

Animals↗
PubMed1996

The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response.

Recent in vitro studies have established that activated B cells express OX40 ligand (L), a member of the tumor necrosis factor/nerve growth factor family of cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig) after cross-linking of OX40L by its counterreceptor OX40, which is expressed on activated T cells. In the present study we investigated the in vivo role of this receptor-ligand pair for the interaction of T and B cells in the course of the T-dependent B cell response against 2,4,6 trinitro-phenyl-keyhole limpet hemocyanin. First, we showed that OX40 is maximally expressed by T cells in the periarteriolar lymphoid sheath (PALS) 3 d after primary immunization. These OX40+ cells are located in close proximity to antigen-specific, activated B cells. Second, we demonstrated that blocking of OX40-OX40L interaction with polyclonal anti-OX40 antibody or with antibodies against certain peptide sequences within its extracellular domain resulted in a profound decrease of the anti-hapten IgG response, whereas the antihapten IgM response was grossly unchanged. Third, we showed that this antibody treatment leads to an inhibition of the development of PALS-associated B cell foci, whereas the formation of germinal centers remained intact. Finally, our data suggest that, whereas B cell memory development was not impaired by anti-OX40 administration, OX40-OX40L interaction seems to be crucial in the secondary immune response. We conclude from these data that the OX40-OX40L interaction in vivo is necessary for the differentiation of activated B cells into highly Ig-producing cells, but is not involved in other pathways of antigen-driven B cell differentiation such as memory cell development in the germinal centers.

Animals↗
PubMed1995

Antibodies to interleukin 12 abrogate established experimental colitis in mice.

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.

Animals↗
PubMed1995

Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells.

OX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells. In the present study, we show that cross-linking of OX40L on CD40L-stimulated B cells, alpha IgD dextran-stimulated B cells, or both results in a significantly enhanced proliferative response with no change in the cell survival rate. Furthermore, OX40 stimulation increases immunoglobulin heavy chain mRNA levels and immunoglobulin secretion, which could not be blocked by anti-cytokine antibodies. In additional molecular studies, we show that OX40L cross-linking results in the down-regulation of the transcription factor BSAP. This, in turn, leads to a change in the in vivo binding pattern of the immunoglobulin heavy chain gene 3' alpha enhancer, suggesting its activation. This effect may thus be one mechanism for OX40-induced increase in immunoglobulin secretion. In conclusion, our data suggest that the OX40-OX40L interaction is a novel pathway in T cell-dependent B cell proliferation and differentiation.

Animals↗
PubMed1995

Dissimilar effect of the carcinogenic agent azaserine on pancreatic and hepatic polyamine metabolism in rats.

The present study was designed to investigate the effects of the carcinogenic agent azaserine on the induction of pancreatic and hepatic polyamine metabolism in rats. One single injection of 30 mg azaserine/kg body weight i.p. is known to induce adenoma and subsequently carcinoma, predominantly in the pancreas, after several months. Male Lewis rats were treated with either azaserine (30 mg/kg body weight i.p.) or saline and 5-10 animals per group were sacrificed 2, 6, 9, 12, 18, 24, and 48 h later. Furthermore, animals were simultaneously treated with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) or the polyamine oxidase inhibitor MDL 72527 and killed 6 and 12 h after azaserine injection. The azaserine-induced significant increase in pancreatic putrescine concentrations was accompanied by an increase in spermidine/spermine N1-acetyltransferase but unchanged ODC and was significantly inhibited by N, N'-bis(2,3-butadienyl)putrescine (MDL 72527) but not by DFMO. S-Adenosylmethionine decarboxylase (SAM-DC) activity was significantly decreased in the pancreata of azaserine-treated animals compared to controls. In contrast, the azaserine-induced significant increase in hepatic putrescine was lower and transient, was accompanied by an increase in ODC and SAM-DC, and was completely inhibited by simultaneous DFMO treatment but not by MDL 72527. These data show completely different patterns of activation of polyamine metabolism in the pancreas and in the liver: Azaserine treatment forms putrescine in the liver by de novo synthesis via ODC only, while azaserine-induced pancreatic putrescine is exclusively produced by the interconversion pathway via oxidation of N1-acetylspermidine.

Animals↗
PubMed1993

Putrescine uptake in rat pancreatic acini: effect of secretagogues and growth factors.

Polyamines [putrescine (Put), spermidine, and spermine] are normal cellular constituents that can modulate cellular proliferation and differentiation in a number of tissue and cell types. Transport is one of the mechanisms that control intracellular polyamine content. The present investigation explores the influence of cholecystokinin (CCK), other secretagogues [carbachol, bombesin, vasoactive intestinal polypeptide (VIP)], insulin, insulin-like growth factor 1 (IGF-1), and epidermal growth factor (EGF) on Put uptake in rat pancreatic acini. Insulin, IGF-1, and EGF stimulated Put uptake by 30-40%. Insulin did not enhance intracellular metabolism of Put. In contrast, CCK and the other secretagogues inhibited this transport system by 40-50% of control (VIP by 23% only). Further investigations of the inhibitory effect of CCK revealed that the maximal uptake rate of Put (Vmax) shifted from 346 pmol [14C]Put/mg DNA-min (control) to 265 pmol [14C]Put/mg DNA-min (100 pM CCK), whereas the Km was only moderately influenced. Augmented Put efflux as well as increased production of endogenous Put (possibly induced by CCK) did not contribute to this change in transport kinetics. In addition, the inhibition of Put uptake induced by CCK was specific and dose dependent up to 100 pM. CCK at 1,000 pM exerted only minor inhibition (20% of control). Incubation with the Ca-ionophore A 23187 did not influence Put accumulation, whereas treatment with the phorbol ester phorbol 12-myristate-13-acetate led to enhanced Put uptake (30-40%). Pretreatment of the acini with 1 mM ouabain led to a reduction of Put uptake by 43%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Putrescine uptake and metabolism in isolated rat pancreatic acini.

In addition to de novo synthesis, polyamine uptake is one of the major mechanisms in the regulation of intracellular polyamine concentrations. The aim of the present study was to investigate the uptake of putrescine (PUT) in isolated rat pancreatic acini and its further metabolic transformation. PUT accumulation was nearly linear over 60 min, showed saturation kinetics with an apparent Km of 3 x 10(-5) M and a Vmax of 346 pmol [14C]-PUT/min/mg DNA and decreased with decreasing temperature. Potassium cyanide (KCN) and dinitrophenol (DNP) inhibited PUT uptake. In the absence of a transmembrane Na+ gradient, PUT uptake decreased by 50%. After 60 min of incubation, 31% of the accumulated [14C]-PUT was metabolized. PUT uptake was stimulated by several amino acids, except for lysine, by decreasing the apparent Km for PUT uptake. PUT accumulation was reduced by spermidine (0.1 mM) by about 90%. Acetylated polyamines had only a minor effect. The release of radioactive material from prelabelled acini was only 10-20% after 90 min.

Amino Acids↗