Biomedical subjects

M Neurath

Publications and source records attributed to M Neurath.

35 records · Page 2Linked to original sources

PubMed1997

Normal interleukin-12 production in individuals with antibodies to Helicobacter pylori.

It is increasingly recognized that the inability of the immune system to clear H. pylori infection is caused by an inadequate immune response and is associated with chronic gastric inflammation. To further investigate the cellular immune response to H. pylori, we studied PBMC from 31 H. pylori antibody-negative and 16 H. pylori antibody-positive individuals for H. pylori-induced DNA synthesis, secretion of the Th1-type cytokine IFN-gamma and secretion of IL-12, a cytokine produced by bacteria-stimulated monocyte/macrophages and a potent inducer of antibacterial immune responses and Th1-type T cells. All experiments were performed using Y. enterocolitica 03 as control. Our results demonstrate that DNA synthesis, IFN-gamma production and IL-12 production induced by H. pylori or Y. enterocolitica 03 did not differ significantly between H. pylori antibody-positive and H. pylori antibody-negative individuals. However, in the H. pylori-positive group there was a tendency, although not statistically significant, to produce less IFN-gamma in response to H. pylori but not Y. enterocolitica. These results demonstrate that monocyte/macrophages from H. pylori-positive individuals secrete normal amounts of IL-12 upon bacterial challenge and suggest that the decreased production of IFN-gamma in H. pylori-positive individuals observed in previous studies is selective for H. pylori and not caused by decreased IL-12 secretion.

Antibodies, Bacterial↗

PubMed1997

Immune responses towards intestinal bacteria--current concepts and future perspectives.

The intestinal mucosa constitutes an important barrier as it separates each individual from a large array of antigens within the bowel lumen. These luminal antigens may either be derived from pathogens or may be derived from harmless constituents such as ingested food or the normal intestinal flora. The dichotomy of potentially harmful and potentially harmless antigens encountered by the mucosal immune system poses the important task that, with regard to bacteria-derived antigens, the gut associated immune system is required to mount an efficient host defense against pathogenic bacteria but to maintain at the same time the regulatory control mechanisms which protect the human organism from hyperresponsiveness, and thus chronic inflammation, towards antigens from the normal intestinal flora. In the present review, we discuss variable host and bacterial factors which are likely to determine whether the immune response to pathogenic or normal intestinal bacteria will have beneficial or detrimental consequences for the human organism. Using infections with the prototype enteropathogens V. cholerae and enteropathogenic E. coli (ETEC), Y. enterocolitica induced reactive arthritis (ReA) and in more detail, inflammatory bowel diseases (IBD) as exemplary clinical situations, we review current hypotheses of how bacteria or their products are encountered by cellular components of the specific immune system and how this may relate to disease pathogenesis and the development of new treatment strategies.

Antigens, Bacterial↗

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

Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5.

In this study, we investigate whether human inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is associated with altered lymphokine secretion profiles, as recently found in various animal models of chronic intestinal inflammation. In initial studies, we determined the proliferative responses of purified lamina propria (LP) CD4+ T cells from patients with IBD under defined conditions of T cell stimulation. We found that IBD LP CD4+ T cells in comparison with control LP CD4+ T cells have diminished TCR/CD3 pathway proliferative responses, whereas CD2/CD28 accessory pathway proliferative responses are relatively preserved. In further studies centering on lymphokine production, we showed that LP T cells from inflamed Crohn's disease mucosa manifest increased IFN-gamma secretion compared with control LP T cells, particularly when stimulated via the CD2/CD28 pathway. Subsequent ELISPOT analysis indicated that this was due to an increased number of IFN-gamma-secreting CD4+ T cells. In contrast, IL-4 and IL-5 production by Crohn's disease LP T cells was decreased compared with that of control LP T cells. Of interest, IL-2 production by Crohn's disease LP T cells was also reduced, as was IL-2 production by peripheral blood T cells. In parallel studies, LP T cells from inflamed ulcerative colitis mucosa stimulated via either the TCR/CD3/CD28 or CD2/CD28 produced increased amounts of IL-5, again when measured either as secreted IL-5 or by ELISPOT analysis. Such increased IL-5 production was not associated with increased IL-4 secretion and, in contrast to Crohn's disease, ulcerative colitis LP T cell production of IL-2 and IFN-gamma was normal. Taken together, these studies provide strong evidence that the immunopathologic process characteristic of the two major forms of IBD is associated with very different cytokine secretion patterns. These different patterns may determine the type of inflammatory process present.

CD2 Antigens↗

PubMed1996

Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.

The recent finding that CD40L on activated T cells induces interleukin (IL) 12 secretion in human peripheral blood monocytes in vitro suggests that the CD40L-CD40 interaction may be of importance in the priming of T helper (Th) 1-type T cells. We therefore investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (2,4,6-trinitrobenzene sulfonic acid [TNBS])-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response prevented interferon gamma production by lamina propria CD4+ T cells and also clinical and histological evidence of disease. In contrast, the secretion of IL-4, a Th2-type cytokine, was increased after anti-gp39 treatment. In further studies we showed that the prevention of disease activity was caused by an inhibition of IL-12 secretion, as demonstrated by immunohistochemistry. In addition, the injection of recombinant IL-12 p70 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. When anti-gp39 was given after the disease was established, no effect on the disease activity was observed. In conclusion, we demonstrated that the CD40L-CD40 interaction is crucial for the in vivo priming of Th1 T cells via the stimulation of IL-12 secretion by antigen-presenting cells (APC).

Animals↗

PubMed1996

Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12.

There is now increasing evidence that hyperresponsiveness towards intestinal flora is a crucial event in the pathogenesis of inflammatory bowel disease (IBD). In support of this hypothesis, we recently described in humans that tolerance exists towards indigenous intestinal flora but is broken in active IBD lesions. In the present study, we have attempted to transfer this model into mice from different genetic backgrounds (BALB/c, SJL/J, C3H/HeJ). We found that mononuclear cells from spleen, small bowel and large bowel of mice do not proliferate, i.e. are tolerant when exposed to bacterial sonicates derived from autologous intestine (BsA) but do proliferate, i.e. are immune when exposed to bacterial sonicates derived from the heterologous intestine of syngenic littermates (BsH). Furthermore, we demonstrate that both local and systemic tolerance to BsA is broken in a murine model of chronic intestinal inflammation induced by the hapten reagent 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), which mimics several important characteristics of Crohn's disease. Tolerance to BsA was restored and TNBS-induced colitis was abrogated in mice systemically treated with interleukin (IL)-10 or antibodies to IL-12. Treatment specifically restored tolerance to BsA, but did not suppress proliferation to BsH. In summary, we here report a new model for the study of immunity and tolerance towards bacterial products. Our data suggest that tolerance to BsA is an important protective mechanism and that restoration of tolerance intestinal flora by IL-10 and antibodies to IL-12 may be of potential therapeutic utility in patients with inflammatory bowel 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↗

PubMed1993

[Acute respiratory failure in tropical malaria during pregnancy. Successful treatment using extracorporeal CO2 elimination].

A 32-year-old woman in the 26th week of pregnancy became ill, 6 days after returning from a trip to Indonesia, with a fever up to 42 degrees C, haemolytic anaemia (haemoglobin 7.6 g/dl) and thrombocytopenia (7,000/microliters). She had not been on any malaria prophylaxis. Chloroquine, quinine and pyrimethamine, administered after macrogametocytes of Plasmodium falciparum had been found in the blood smear, eliminated the parasites from the peripheral blood, but respiratory failure and treatment-resistant pneumonia occurred, leading to the adult respiratory distress syndrome (Morel stage 4). Because of threatened intrauterine death (resulting from premature placental separation during artificial ventilation) the child was delivered by an emergency section. Despite extensive conventional therapeutic measures the mother's respiratory state progressively deteriorated so that extracorporeal membrane CO2 elimination was instituted on the 17th day. First signs of improvement in respiratory functions were noted after six days. The extracorporeal CO2 elimination was discontinued after twelve days, because artificial ventilation could now be adequately controlled. The woman was gradually weaned from the ventilator and discharged home without symptoms after a total of 11 weeks in hospital. Her child has not shown any neurological symptoms.

Acute Disease↗

PubMed1993

Partial hepatectomy affects pancreatic size and function in rats.

The effect of partial hepatectomy (62 +/- 2% of liver mass) or sham laparotomy on the pancreas was studied in rats. Pancreatic contents of DNA, protein, and digestive enzymes were measured 14 days postoperatively. Pancreatic acini were prepared to study exocrine pancreatic function after hormonal stimulation. Islet hormone release was investigated in the isolated perfused pancreas. Liver regeneration reached 93 +/- 1% within 14 days. Water contents in liver and pancreas remained unaltered. Simultaneously, the pancreatic weight increased significantly. Pancreatic enzymes showed a parallel elevation, whereas DNA remained unaffected. Amylase secretion from pancreatic acini was unaltered. Stimulated insulin and somatostatin release from the perfused pancreas were both increased. Plasma cholecystokinin levels were elevated, whereas neurotensin was decreased. Insulin and gastrin remained unchanged. In conclusion, after partial hepatectomy, enhanced cholecystokinin and decreased neurotensin blood levels are suggested to contribute to a hypertrophic effect on the exocrine pancreas and an adaptive regulation of the endocrine gland.

Amylases↗

PubMed1993

Brucellosis: differential diagnosis of acute abdominal pain.

A 34-year-old Turkish woman presented with septic fever, sweats, arthralgia, and abdominal pain. Further examination revealed generalized lymphadenopathy, hepatosplenomegaly, pancytopenia, and multiple caseous granulomas. Microbiological diagnosis revealed Brucella melitensis type 3 as causative agent. This case report demonstrates that abdominal pain can be a symptom in brucellosis, and caseous granulomas may occur. In our mobile society Brucella infection should be considered as possible differential diagnosis in patients with fever, lymphadenopathy, hepatosplenomegaly, and pancytopenia, although human brucellosis is rare in Germany and other Western countries.

Abdominal Pain↗

PubMed1992

[Fascicular and sub-fascicular architecture of the cruciate ligament].

The details of the collagen fascicle morphology and the vascularization of the anterior and the posterior cruciate ligament were examined by the combined use of histology, transmission- and scanning electron microscopy, morphometry and immunohistochemistry. The diameters of the collagenous fibrils in the anterior cruciate ligament ranged between 20 and 155 nm (x = 74 nm, s = 18.8 nm) and in the posterior cruciate ligament between 20 and 175 nm (x = 82 nm, s = 25.4 nm). Type III and VI collagen were found distributed throughout the matrix but concentrated in the attachment regions of the ligaments. The content of type IV collagen in the anterior cruciate ligament was low. The amount of arterioles revealed a typical pattern (anterior cruciate ligament: less than 30 years = 2.94/mm2, greater than 90 years = 2.02/mm2, proximal = 3.15/mm2, distal = 2.18/mm2; posterior cruciate ligament: less than 30 years = 4.69/mm2, greater than 90 years = 3.87/mm2, proximal = 4.08/mm2, distal = 3.98/mm2).

Adult↗

PubMed1992

Intraoperative ultrasonography in surgery for chronic pancreatitis.

We report our experience with intraoperative ultrasonography in 49 patients undergoing surgery for chronic pancreatitis. Among drainage procedures, there were 14 laterolateral pancreaticojejunostomies, 15 pseudocystojejunostomies, and 2 pseudocystoduodenostomies. Under the guidance of intraoperative ultrasonography, left sided partial resection of the pancreas was performed in 7 patients, whereas a Whipple-type procedure was necessary in 6 cases. All preoperatively diagnosed pseudocysts, abscess formations, and dilated pancreatic ductal systems could be easily localized with the assistance of intraoperative ultrasound. Additionally to diagnoses already made preoperatively, intraoperative ultrasonography revealed a second, smaller pseudocyst in one patient and pancreaticolithiasis in another case. However, significant assistance and comfort to the operating surgeon was provided in all cases by intraoperative ultrasound imaging. This technique, which is cost effective and minimally invasive, proved to be extremely helpful in localizing pancreatic fluid collections and the course of the pancreatic duct. It facilitates the operation by reducing tissue traumatization and operative time. In experienced hands, intraoperative ultrasonography is a reliable method and a useful adjunct to the surgeon.

Adult↗

PubMed1992

[New aspects of the functional anatomy of the menisci].

The present study concerned 16 human menisci: light, transmission (TEM) and scanning electron microscopic (SEM) techniques were used in addition to histochemical examinations, to define the microstructure of their collagenous fibre systems. A characteristic arrangement of the fibrils was noted. The diameters of the collagen fibrils ranged between 20 and 190 nm in the medial meniscus, the mean value being 67.5 nm (lateral: 70 nm). Many collagen type VI fibrils were detected, and collagen type IV was present. Such an organization has implications for knee joint stability, the variability of the fibril diameters and the characteristic arrangement giving the tissue great tensile stiffness and allows adaptation to all physiological loading conditions. On the surface of the menisci openings of canal-like structures were noted. Their characteristic distribution indicates that they carry nutrients from the synovial fluid to the normal avascular areas of the menisci.

Actin Cytoskeleton↗

PubMed1991

[Comparative microstructural studies on collagen and elastic fiber systems of the cruciate ligaments].

The aim of the present study was to compare the collagenous fibre systems of the anterior (ACL) with the posterior cruciate ligament (PCL). 22 cruciate ligaments were examined by the combined use of light-, transmission- and scanning electron microscopy. Characteristic interligamental differences were established. ACL: more anchoring type VI collagen, thinner but more branched fibrils, complex collagen networks, much more elastic elements. PCL: more type IV collagen, many intrinsic vessels, thicker fibrils, parallel fibre arrangement. The results indicate that the ACL is exposed at the first line to rotational forces, the PCL probably more to tensional forces. The collagen fibre arrangement of the cruciate ligaments is to take into consideration by the surgeon.

Adult↗

PubMedDate not supplied

Correlative histologic and arthroscopic evaluation in rheumatoid knee joints.

The correlation between arthroscopic observations and histologic changes in rheumatoid arthritis is still controversial. Synovial samples of 21 knee joints in rheumatoid arthritis patients were comparatively investigated by endoscopy and histology. Biopsies were scored by an endoscopist and subsequently dissected. Different histochemical and immunocytochemical staining techniques were used to define inflammatory activity. Arthroscopic and histological values were compared by rating scales and variance analysis. Our study indicates that synovial biopsy is of diagnostic value in rheumatoid arthritis. However, its usefulness depends on the histochemical methods used. The results revealed highly significant correlations of endoscopic features with the number of neutrophilic granulocytes, intravascular leukocytes, and peroxidase-positive macrophages. However, no relationship was found between the detection of lymphocytes or resident macrophages and inflammatory scores. The close correlation between endoscopic and histological findings suggests that arthroscopic evaluation allows a valuable classification of the inflammatory activity in rheumatoid synovitis.

Arthritis, Rheumatoid↗

PubMedDate not supplied

[Expression of tenascin, laminin and fibronectin following traumatic rupture of the anterior cruciate ligament].

In the present study, the pattern of some extracellular matrix glycoproteins was determined in traumatic anterior cruciate ligament ruptures (n = 17) and in normal ligaments (n = 11). 6 microns cryo-sections were incubated with monoclonal antibodies recognizing tenascin, laminin, and fibronectin, and FITC-labeled secondary antibodies. Immunohistochemistry revealed that tenascin, fibronectin and laminin are sparsely distributed in normal anterior cruciate ligaments, but strongly expressed in ruptured ligaments with a time-restricted pattern. The de novo-expression of tenascin appeared before laminin but later than fibronectin. The data suggest that fibronectin and tenascin are important, partially antagonistic components during healing processes after anterior cruciate ligament ruptures.

Adolescent↗

PubMedDate not supplied

[Differences in condition between the anterior and posterior cruciate ligament in rheumatoid arthritis].

In rheumatoid arthritis (RA) we examined the cruciate ligaments of 16 patients by the use of light- and transmission electron microscopy. Considerable differences between the anterior (ACL) and the posterior cruciate ligament (PCL) were observed. The ACL showed dramatic ultrastructural changes, against that the PCL was compact and well conserved. The preservation of PCL in joint surgery can morphologically be recommended. Perhaps the greater inflammatory process on the surface of ACL is responsible for the observed differences.

Aged↗