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Biomedical subjects

M Feldmann

Publications and source records attributed to M Feldmann.

At least 55 records · Page 3Linked to original sources
PubMed1992

TNF alpha--a pivotal role in rheumatoid arthritis?

This review seeks to describe data which support the concept that TNF alpha has a pivotal role in the pathogenesis of RA. There is now compelling evidence from in vitro studies and in animal models that this is the case. The in vitro studies suggest that the direct pathogenic effects of TNF alpha are amplified by its potential to act as a potent paracrine molecule, by inducing other pro-inflammatory molecules such as IL-1, and GM-CSF. It has yet to be established whether similar paracine effects of TNF-alpha are observed in the collagen type II mouse, or in human TNF alpha transgenic mice, where (as discussed in this review), TNF alpha undoubtedly has a pathogenic involvement. During the ongoing inflammation in RA, TNF alpha (and other mediators?) induce the production of soluble TNF-R which can act as natural inhibitors. This process is, however, inadequate within the inflamed synovium, due to the fact that cytokine interactions are very local, through autocrine and paracrine mechanisms. In this environment there is a continuous competition between the interactions of surface or soluble receptor with TNF alpha. It may well be that soluble TNF-Rs play a more important role in the periphery where they act as an essential clearance mechanism for the ligand. If, as the available data suggest, TNF alpha does indeed have a pivotal role in the pathogenesis of RA, this needs to be verified by demonstrating that removal of TNF alpha locally in the synovial joint of RA patients has a significant effect on clinical parameters of disease, and the progression of the disease process itself.

Arthritis, Rheumatoid↗
PubMed1992

Distribution of interleukin 1 receptor antagonist protein (IRAP), interleukin 1 receptor, and interleukin 1 alpha in normal and psoriatic skin. Decreased expression of IRAP in psoriatic lesional epidermis.

The distribution of interleukin 1 alpha (IL-1 alpha), type 1 interleukin 1 receptor (IL-1R), and the interleukin 1 receptor antagonist protein (IRAP), was investigated in biopsies of normal skin, and in uninvolved and lesional skin of patients with psoriasis, using specific monoclonal antibodies. We report the novel finding that IRAP is distributed throughout the living layers of the epidermis in normal skin, and is also associated with sebaceous glands and eccrine sweat glands. Our finding that the inhibitor protein IRAP is present in areas where the pro-inflammatory cytokine IL-1 alpha is distributed provides strong evidence in favour of a cytokine regulatory system in normal skin. We further document for the first time that IL-1R in normal skin is localized to the living layers of the epidermis, sebaceous and eccrine glands, as well as to a prominent network of dermal dendritic cells, and upper dermal blood vessels. There was a consistent reduction in the level of IRAP expression in lesional compared with uninvolved skin in biopsies from six out of seven psoriasis patients. Decreased IRAP expression in lesions of psoriasis indicates that alterations in the level of this inhibitor protein may be important in the pathogenesis of inflammatory skin conditions.

Epidermis↗
PubMed1992

Detection of cytokines at the site of tuberculin-induced delayed-type hypersensitivity in man.

Cytokines are chiefly local mediators which play an important role in the regulation of the cell-cell interactions which may be involved in the development of the delayed-type hypersensitivity (DTH) reaction. Using immunohistochemical techniques, the presence of IL-1 alpha, IL-1 beta, IL-6, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) in the skin in tuberculin-purified protein derivative (PPD)-induced DTH reactions was investigated in six normal individuals. Cells staining for these cytokines were first observed 6 h after PPD challenge, and they were detected throughout the duration of the 7-day experiment. The number of cells staining for IFN-gamma reached a peak at 48 h, where 33% of the total aggregate cells were positive, but declined thereafter to 3% at day 7. On the other hand, the number of cells staining for TNF-alpha and IL-1 persisted at high levels throughout the observation period of 7 days (e.g. at 48 h and thereafter, about 40% cells positive for TNF-alpha and 20% for IL-1 alpha and IL-1 beta). Double immunofluorescence and staining on sequential sections showed that IFN-gamma-staining cells were CD3+ T cells; TNF-alpha, IL-1 and IL-6 staining cells were mainly of the CD68+ macrophages/monocytes and that 80% of the CD1a+ cells (Langerhans-like cells) in the dermis contained TNF-alpha and IL-1. The presence of these cytokines at the site of inflammation suggests that they may be locally produced by the inflammatory cells. Their persistence during the reaction suggests that they are intimately associated with this response, and are involved in the development of the reaction.

B-Lymphocytes↗
PubMed1992

Cytokine receptors: structure and signal transduction.

In the past 2-3 years, a number of cytokine receptors have been partly characterized and the cDNAs for the ligand binding chains cloned. This has revealed that cytokine receptors are complex. Many are known to be multichain receptors (e.g. IL-2) and since their mechanism of signal transduction is not obvious, it is likely that other proteins yet to be defined take part in the signalling process. The cloning of the receptor ligand binding chain has revealed that (unlike cytokines), there are major families of receptors. Some are members of the Ig supergene family (e.g. IL-1 receptor), others are members of the nerve growth factor receptor family (e.g. TNF), but the majority are members of the haematopoietic growth factor family (e.g. IL-3, GM-CSF). Yet other cytokine receptors do not belong to a family, e.g. IFN-gamma.

Amino Acid Sequence↗
PubMed1992

HER2 (c-erbB-2) oncoprotein expression in colorectal adenocarcinoma: an immunohistological study using three different antibodies.

Paraffin wax sections of 70 surgically resected colorectal adenocarcinomas were examined for the overexpression of HER2/c-erbB-2 oncoprotein using three different specific antibodies and the avidin-biotin immunoperoxidase technique. The patients included 38 men and 32 women aged between 47 and 80 years. The tumours were derived from various parts of the large intestinal tract, and represented all three stages of Dukes' classification and the three histological grades of differentiation. Many tumour sections also included adjacent normal or transitional mucosa. Eight tubular adenomas found in the colectomy specimens in association with some carcinomas were also examined. No positive membrane staining was seen in any of the 70 carcinomas, four adenomas, two hyperplastic polyps, nor in the adjacent normal or transitional mucosa. It is suggested that the overexpression of c-erbB-2 gene product is unlikely to be as common and as pronounced in colorectal adenocarcinoma as it is in ductal carcinoma of the breast.

Adenocarcinoma↗
PubMed1992

[Neonatal Campylobacter fetus septicemia: a case secondary to maternal-fetal contamination].

A favourable outcome of a severe Cambylobacter fetus sepsis in a neonate is reported. The transmission was probably vertical. His mother experienced diarrhoea 15 days before birth. No infecting organism was isolated from maternal stools, but maternal antibody response was significant. Such a perinatal infection with meningitis and septicemia is uncommon. Bacteriological diagnosis requires an enriched medium and a long incubation. The diagnosis should be evoked in view of an anamnestic context, a negative culture or a resistance to antimicrobial drugs.

Bacteremia↗
PubMed1992

[Bourneville tuberous sclerosis manifested by prenatal finding of intracardiac tumors].

Neonatal cardiac rhabdomyoma is the most frequent cardiac tumour in the newborn, and a classical way to diagnose tuberous sclerosis (Bourneville's disease). The authors report 4 cases, including 2 antenatal diagnosis: 2 of them had arrhythmia, one with asystolic cardiac failure and the other with cyanosis due to a right-left shunt; the tumour was asymptomatic in the 2 others. The 4 babies had clinical and radiological neurologic signs of tuberous sclerosis, initially or during the course of the disease. The authors discuss the polymorphism of the clinical presentation of tuberous sclerosis in the newborn. Although tuberous sclerosis is transmitted through a dominant gene, the expressivity and the penetrance are very variable. The authors discuss the examination and investigation of at risk family members. The genetic counsel is difficult but very important because of the poor neurologic prognosis of the disease.

Female↗
PubMed1992

Detection of in vivo production of tumour necrosis factor-alpha by human thyroid epithelial cells.

We have established previously that human thyroid epithelial cells (TEC) from patients with autoimmune thyroiditis are able to synthesize cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6). This paper examines TEC in sections from autoimmune thyroiditis for the in vivo production of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) using the combined techniques of in situ hybridization and immunohistochemistry. Thyroid tissue from patients with Graves' disease, Hashimoto's disease and non-toxic goitre was examined and both mRNA and the protein of TNF-alpha were detected in TEC on frozen sections. Representative figures of only Graves' samples are illustrated in this paper. In contrast, using the same methods, IFN-gamma was detected only in the infiltrating cells and not in TEC of thyroid tissue from the patients.

Epithelium↗
PubMed1992

[Droperidol versus metoclopramide. Prevention of emesis following strabismus surgery in children].

Vomiting after strabismus surgery is a major problem that remains as yet unsolved, especially in children. Droperidol and metoclopramide, both known as powerful antiemetic drugs, were compared in this study. METHODS. One hundred ASA class I and II children ranging from 3 to 10 years of age were studied in a double-blind, randomised fashion. They were assigned to three groups: group D (n = 33) received 0.075 mg/kg droperidol, group M (n = 33) 0.15 mg/kg metoclopramide, and group N (n = 34) 0.1 ml/kg NaCl i.v. upon arrival in the post-anaesthesia recovery room (PARR). After oral premedication with 0.4 mg/kg midazolam, anaesthesia was induced via a face mask by inhalation of halothane, nitrous oxide, and oxygen. Barbiturates, atropine, and succinylcholine were not used; 0.05 mg/kg vecuronium was given to facilitate intubation. Gastric contents were aspirated by a gastric tube at the end of the operation. Vomiting and retching were recorded for 24 h; recovery from anaesthesia was assessed by a modified Steward score. RESULTS. The three groups were comparable regarding age, body weight, duration of anaesthesia, number of repaired eye muscles, and occurrence of the oculocardiac reflex (OCR). During the first 24 h postoperatively 21/33 (64%) patients of group D vomited, 24/33 (73%) of group M, and 33/34 (97%) of group N. The differences between groups D and N and between M and N were significant (P less than 0.01); comparison of groups D and M showed no statistical significance. Droperidol was more effective in reducing severe vomiting. Of the group N children, 47% vomited more than 6 times in 24 h compared to 18% of group M and 0% of group D. Age, sex, duration of anaesthesia, number of repaired eye muscles, and occurrence of the OCR had no influence on postoperative vomiting. Despite being administered at the end of the operation, droperidol did not prolong the patients' stay in the PARR. The post-anaesthetic scores for group D children were only slightly lower compared to groups M and N. CONCLUSIONS. Droperidol (0.075 mg/kg) and metoclopramide (0.15 mg/kg) both reduce postoperative vomiting after strabismus surgery. Droperidol seems to be more effective in reducing severe vomiting. Postoperative sedation after droperidol was not a major problem in our experience.

Child↗
PubMed1991

Regulatory interactions among autologous T cell clones. Human bifunctional T cell clones regulate the activity of an autologous T cell clone.

In contrast to the ease of cloning and characterizing, at the molecular level, helper and cytotoxic T cells, suppressor T cells remain an enigma, and their existence as discrete entities is being increasingly challenged. Here we review evidence that CD4+ regulatory clones, capable of expressing both helper and suppressor functions, may account for much of the suppressor function. It is suggested that a single T cell clone, depending on the signals it receives from its environment, may release either helper or suppressor cytokines. Studying such clones under defined conditions (providing suppressor signals), may preclude detection of their helper capacity. Since some therapeutic approaches in various human diseases are based on the manipulation of helper and suppressor functions, the question whether committed suppressor cells exist has important practical implications in medicine.

Clone Cells↗
PubMed1991

Platelet-derived interleukin 1 induces human endothelial adhesion molecule expression and cytokine production.

Interleukin 1 (IL-1) plays a central role in the regulation of the body's response to infectious and inflammatory stimuli. Recent evidence has shown that human platelets express a cell associated form of this proinflammatory cytokine very rapidly following activation. Since one of the earliest events in inflammation is frequently the rapid adhesion of platelets to injured endothelium, it was of interest to determine whether platelets express IL-1 in a functionally relevant form that can alter the phenotype of human endothelial cells in vitro. Thrombin activated platelets induced significant expression of the adhesion molecule intercellular adhesion molecule 1, as well as secretion of the IL-1 inducible cytokines IL-6 and granulocyte macrophage colony stimulating factor by cultured human umbilical cord and saphenous vein endothelial cells. This was inhibited by prior treatment of the platelets with antibody specific for IL-1. These results suggest that platelet delivered IL-1 might initiate and regulate some of the earliest phases of the inflammatory response. An additional observation of interest was differential induction of endothelial leucocyte adhesion molecule 1 by activated platelets on saphenous vein but not umbilical vein but not umbilical vein endothelial cells, which suggests functional heterogeneity of the endothelial cells.

Adult↗
PubMed1991

Autoantigen recognition by thyroid-infiltrating T cells in Graves disease.

Graves disease is a common form of human autoimmune thyroiditis. It shares many pathological features and HLA associations with other, less easily studied, organ-specific autoimmune conditions such as insulin-dependent diabetes mellitus, and hence it is also a useful model for understanding these other diseases. We have previously shown that thyroid-infiltrating T cells in Graves disease that have been recently activated in vivo specifically recognize autologous thyroid epithelial cells. However, the autoantigens involved were not defined. In this study, we have made use of antigen-independent T-cell cloning techniques to show that at least three different thyroid antigens, three different epitopes on a single antigen, and two HLA class II elements are involved in this recognition process in a single individual. This demonstrates that T cells that are present and activated at the site of a human autoimmune disease may show considerable heterogeneity in their recognition of autoantigen on the target tissue. This contrasts with the limited heterogeneity recently reported in some animal models and has potentially important implications for both our understanding of the autoimmune process in humans and the design of immunotherapies to reverse it.

Adult↗
PubMed1991

Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis.

Using immunoaffinity-purified polyclonal anti-human recombinant tumor necrosis factor alpha (TNF alpha) F(ab')2 fragments and immunohistochemical techniques, the cells that make TNF alpha were localized in the inflamed synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Anti-TNF alpha antibody-stained cells were demonstrated in 9 of 11 RA and 2 of 4 OA but none of 5 normal synovial membranes examined. In RA, 26-64% of the lining layer cells were positive for TNF alpha. In the interaggregate area, 10-30% of the cells contained TNF alpha, often in a perivascular distribution, and up to 19% of the cells in lymphoid aggregates stained for TNF alpha. Some endothelial cells also stained with these antibodies. In OA tissues, the TNF alpha-containing cells were found predominantly in the deeper layer. Cells containing TNF alpha were also found at the cartilage-pannus junction in all 4 RA specimens examined. Double immunofluorescence analysis demonstrated that most TNF alpha-secreting cells in the RA synovial membrane expressed the monocyte/macrophage marker antigens CD11b and CD14, and a few expressed the T cell marker CD3. Our findings provide histologic evidence that TNF alpha is locally produced in the lining and deeper layers of the synovium by cells of the monocyte/macrophage lineage, supporting its role in inflammation. Further, our findings demonstrate that TNF alpha is produced by cells at the cartilage-pannus junction, which could affect chondrocyte metabolism, leading to the cartilage degradation in RA.

Antibodies↗
PubMed1991

Interleukin 4 induces interleukin 6 production by endothelial cells: synergy with interferon-gamma.

Interleukin (IL)4 induces IL6 production by human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner, as shown by bioassay and immunoprecipitation. Interferon (IFN)-gamma, which antagonizes IL4 effects on leukocytes, synergized with IL4 in the induction of IL6 production by HUVEC. Contamination with endotoxin was excluded by heat-inactivated IL4, preincubating with anti-IL4 polyclonal antibody and the use of polymyxin B. The presence of IL4 receptors on HUVEC was shown by affinity cross-linking with 125I-IL4, revealing a 110-kDa binding protein. However, compared with the amount seen on T cells the 60-70-kDa cross-linked doublet was present at much lower levels. Additional lower molecular weight cross-linked proteins were isolated only with HUVEC, but the origin of these is unclear. IL6 is a pluripotent cytokine produced by many cells which promotes the differentiation and growth of lymphocytes and the production of acute phase protein by hepatocytes, and is important in the regulation of immunity at the systemic and local levels. Since IL4 and IFN-gamma are produced by T cells, which are frequently associated with vascular endothelium during chronic inflammation, IL4 is likely to be an important cytokine in the regulation of IL6 and perhaps other cytokine production by endothelium in vivo.

Drug Synergism↗
PubMed1991

Induction of the interleukin 1 receptor antagonist protein by transforming growth factor-beta.

Transforming growth factor-beta 1 (TGF-beta 1) mediates many immunosuppressive effects on immune cells and can inhibit the production of tumor necrosis factor and interleukin 1 (IL 1). However, TGF-beta 1 can stimulate the production of IL 6 and platelet-derived growth factor, indicating that TGF-beta 1 initiates complex effects on the production of cytokines. In this report we show that treatment of peripheral blood monocytes with TGF-beta 1 leads to the induction of a recently described IL 1 receptor antagonist protein (IRAP). The effect of TGF-beta 1 was both dose and time dependent. TGF-beta 1 induced de novo synthesis of IRAP, as Northern blotting experiments indicated a rapid and transient induction of the mRNA encoding IRAP. The induction of IRAP suggests a potential mechanism by which some of the inhibitory effects of TGF-beta 1 are mediated.

Cells, Cultured↗
PubMed1991

Cloning, expression and cross-linking analysis of the murine p55 tumor necrosis factor receptor.

Tumor necrosis factor (TNF) mediates its pleiotropic effects via high-affinity cell surface receptors. In man, molecular cloning has identified two distinct, independent TNF receptors (TNFR) of 55 and 75 kDa. It is unclear, however, whether the multiple effects of TNF are suggested between the receptor types. In the mouse, previous studies had shown functional heterogeneity of TNFR, since the WEHI 164 fibroblast line is sensitive to the cytotoxic effects of both murine and human TNF, whereas the murine T cell line, CT6, proliferates in response to murine but not human TNF. In this study, the cloning of a cDNA encoding the murine homologue of the p55 TNFR is reported. This receptor binds murine and human TNF with equal affinity and is expressed on WEHI 164 and a number of other cell lines, but only low levels of mRNA and no protein is detectable on CT6 cells. CT6 cells, however, express a second TNFR of approximately 75 kDa, identified by cross-linking analysis, which is also found on WEHI 164 cells, and binds only murine TNF. These studies establish that there are also two TNFR in the mouse, and suggests that there may be segregation of the cytotoxic and proliferative responses between different receptors, at least in these cell lines.

Amino Acid Sequence↗