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Biomedical subjects

H U Simon

Publications and source records attributed to H U Simon.

At least 73 records · Page 4Linked to original sources
PubMed1996

Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils.

In allergic diseases, the cytokines interleukin (IL)5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are upregulated and have been proposed to cause blood and tissue eosinophilia by inhibition of eosinophil apoptosis. We demonstrate herein, in freshly isolated human eosinophils, that the IL-3/IL-5/GM-CSF receptor beta subunit interacts with cytoplasmic tyrosine kinases to induce phosphorylation of several cellular substrates, including the beta subunit itself. The Lyn and Syk intracellular tyrosine kinases constitutively associate at a low level with the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils. Stimulation with GM-CSF or IL-5 results in a rapid and transient increase in the amount of Lyn and Syk associated with the IL-3/IL-5/GM-CSF receptor beta subunit. Lyn is required for optimal tyrosine phosphorylation and activation of Syk. In contrast, Syk is not required for optimal tyrosine phosphorylation and activation of Lyn. These data suggest that Lyn is proximal to Syk in a tyrosine kinase cascade that transduces IL-3, IL-5, or GM-CSF signals. Compatible with this model, both Lyn and Syk are essential for the activation of the antiapoptotic pathway(s) induced through the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils.

Apoptosis↗
PubMed1996

Expansion of cytokine-producing CD4-CD8- T cells associated with abnormal Fas expression and hypereosinophilia.

The mechanisms of sustained overproduction of eosinophils in the idiopathic hypereosinophilic syndrome and in some human immunodeficiency virus (HIV)-1-infected individuals are largely unknown. We hypothesized that T cells may release soluble products that regulate eosinophilia in these patients, as has been previously shown in bronchial asthma. We identified one patient with idiopathic hypereosinophilic syndrome and one HIV-1-infected individual with associated hypereosinophilia who demonstrated high numbers of CD4-CD8- T cells in peripheral blood. CD4-CD8- T cells from both patients, although highly activated, did not express functional Fas receptors. In one case, the lack of functional Fas receptors was associated with failure of Fas mRNA and protein expression, and in another, expression of a soluble form of the Fas molecule that may have antagonized normal signaling of Fas ligand. In contrast to the recently described lymphoproliferative/autoimmune syndrome, which is characterized by accumulation of CD4-CD8- T cells and mutations within the Fas gene, this study suggests somatic variations in Fas expression and function quite late in life. Both genetic and somatic abnormalities in regulation of the Fas gene are therefore associated with failures to undergo T cell apoptosis. Furthermore, the expanded population of CD4-CD8- T cells from both patients elaborated cytokines with antiapoptotic properties for eosinophils, indicating a major role of these T cells in the development of eosinophilia. Thus, this study demonstrates a sequential dysregulation of apoptosis in different cell types.

Acquired Immunodeficiency Syndrome↗
PubMed1996

A case of hypereosinophilic syndrome is associated with the expansion of a CD3-CD4+ T-cell population able to secrete large amounts of interleukin-5.

Interleukin-5 (IL-5) is the major soluble factor able to mediate hypereosinophilia. We report a case of hypereosinophilic syndrome in which the presence of a population of CD3-CD4+ cells able to overproduce IL-5 was shown. The lack of CD3 and TCRAB membrane expression on otherwise phenotypically normal mature T lymphocytes together with the absence of detectable TCRBV mRNA and clonal rearrangement of TCRB gene suggested that the abnormal lymphocyte population was the expression of a peripheral T-cell lymphoma with an indolent clinical course. Peripheral blood lymphocytes enriched in this population were able to secrete high levels of IL-5 but not IL-4, and no IL-2 or interferon-gamma, when stimulated in vitro with phytohemagglutinin and phorbol myristate acetate. The serum contained eosinophil survival factors whose activity was partially neutralized by a specific antihuman IL-5 antibody. This observation further emphasized the relationship between hypereosinophilic syndrome. IL-5, and T-cell lymphoproliferative disorders.

Aged↗
PubMed1996

Expression and function of the Fas receptor on human blood and tissue eosinophils.

The interaction between activated T cells and eosinophils has been proposed to play an important role in the pathogenesis of allergic diseases. T cell-derived cytokines such as interleukin-5 and granulocyte/macrophage colony-stimulating factor inhibit eosinophil apoptosis and may therefore contribute to the development of tissue and blood eosinophilia in these disorders. Withdrawal of these cytokines leads to eosinophil apoptosis in vitro. In contrast, the mechanisms which actively induce apoptosis in eosinophils are at present not completely understood. In this study, we demonstrate that freshly isolated human eosinophils express mRNA and protein for the Fas receptor. Using anti-Fas monoclonal antibody (mAb), we show that Fas activation accelerates apoptotic eosinophil death in vitro. Moreover, treatment of nasal polyps ex vivo with anti-Fas mAb decreased eosinophilic tissue inflammation. However, we observed that blood as well as tissue eosinophils derived from some eosinophilic donors do not express functional Fas receptors, although Fas protein is normally expressed in these cells. This implies that the susceptibility of the Fas receptor is a matter of regulation in eosinophils as previously observed in other systems. These data suggest that Fas ligand/Fas interactions are involved in the regulation of eosinophil apoptosis and that defects in this system could contribute to the accumulation of these cells in allergic and asthmatic diseases.

Antibodies, Monoclonal↗
PubMed1996

Long-term outcome of idiopathic hypereosinophilic syndrome--transition to eosinophilic gastroenteritis and clonal expansion of T-cells.

We describe a patient with idiopathic hypereosinophilic syndrome, without initial gastrointestinal symptoms, and their transition to eosinophilic gastroenteritis. This patient, a 65-year-old man, presented with fever, constitutional symptoms, peripheral and bone marrow eosinophilia 20 years ago. During the course of the disease, diarrhoea and malabsorption became prominent, whereas bone marrow eosinophilia regressed completely and blood eosinophilia regressed partially. Biopsies showed a severe eosinophilic gastroenteritis of the mucosal type involving the stomach, small bowel and colon. During the final years of the patient's disease, mucosal eosinophilia became less intense and a mucosal infiltration with T-cells dominated. At autopsy, immunopathological studies of small intestines and colon specimens showed a clonal expansion of morphologically normal T-cells in the intestinal mucosa, which expressed the abnormal phenotype CD2+CD3+CD4-CD5-CD8-. Flow cytometry examination of peripheral blood revealed a corresponding abnormal population of CD3+CD4-CD8- T-cells, indicating a systemic spread of the process. The patient eventually died of non-obstructive small bowel infarction with peritonitis 20 years after the onset of the first symptoms. We postulate that the destructive eosinophilic/lymphocytic inflammation is caused by a clonal proliferation of T-lymphocytes with probable secretion of Type 2 T(helper) cell cytokines and consecutive stimulation of eosinophils.

Aged↗
PubMed1996

Novel therapeutic strategies via the apoptosis pathways to resolve chronic eosinophilic inflammation.

Physiologic cell death is a necessary process to maintain correct cell numbers. Alterations in this process may contribute to the pathogenesis of a number of human diseases. During the past few years, evidence has been adduced indicating that eosinophilic disorders are associated with a defect in eosinophil apoptosis. Here we review our recent progress in understanding the processes regulating eosinophil apoptosis, and the implications of these results for novel therapeutic possibilities.

Journal Article↗
PubMed1995

IL-8 is expressed by human peripheral blood eosinophils. Evidence for increased secretion in asthma.

Eosinophils possess the capacity to synthesize various cytokines. We demonstrate that IL-8 mRNA and protein are constitutively expressed by freshly isolated resting human eosinophils. Most of the patients with bronchial asthma or atopic dermatitis show evidence for up-regulated IL-8 protein expression in eosinophils but not in neutrophils, suggesting that an eosinophil-specific cytokine may act in these patients. To investigate whether the intracellular IL-8 can be released, eosinophils were stimulated by different cytokines and platelet-activating factor. Priming with granulocyte-macrophage CSF and a subsequent 25-min stimulation with RANTES or platelet-activating factor resulted in release of IL-8 from highly purified human eosinophils in vitro. As the eosinophil is the predominant cell in asthmatic inflammation, we determined IL-8 concentrations in bronchoalveolar lavage fluids from normal individuals and asthmatic patients. Bronchoalveolar lavage fluids from patients with bronchial asthma consistently demonstrated high IL-8 concentration compared with the controls. This suggests that IL-8 is released in vivo by inflammatory bronchial cells in asthma.

Asthma↗
PubMed1995

Phenomenology, pathogenesis, diagnosis and treatment of aspirin-sensitive rhinosinusitis.

Aspirin-sensitive rhinosinusitis is a non-allergic, non-infectious perennial eosinophilic rhinitis starting in middle age and rarely seen in children. It may also been seen in atopic patients who have developed a mixed type rhinitis with recurrent airway infections. There is an intolerance to aspirin and most other NSAID. An intolerance to tartrazine, food additives, alcohol, narcotics and local anaesthetics can follow. Most aspirin-sensitive patients develop nasal polyps. Untreated, it can lead to asthma. The frequency of aspirin intolerance is 6.18% in patients with perennial rhinitis and 14.68% in patients with nasal polyps. Immunologic studies of the blood and the nasal polyps show a hyperreactive immune system with an activation of the eosinophil granulocytes due to a TH1-lymphocyte-activation. In atopic subjects with a mixed type rhinitis, we found a TH2- and B-lymphocyte-activation as well. Inhibition of eosinophil apoptosis might be a second remarkable change in the immune system of aspirin-sensitive patients. A key pathogenic event for aspirin sensitivity is the change of the leukotriene pathway for arachidonic acid metabolism releasing high amounts of leukotrienes LTC4, LTD4 and LTE4, effective chemoattractants and activators of inflammatory cells. For the diagnosis of aspirin intolerance, nasal, bronchial and oral challenge are available. The sensitivity of nasal challenge with lysine-aspirin for the diagnosis of aspirin-sensitive rhinitis is 0.93, the specificity 0.97. It is the safest test in aspirin-sensitive asthmatics causing bronchial side effects only in 0.45%. Therapy of aspirin-sensitive rhinosinusitis includes avoidance of aspirin and NSAID. A general down regulation of the immune response with glucocorticosteroids is an effective means. We prefer a maintenance dose of budesonid 400 micrograms a day. Systemic steroids for a reversibility test or in exacerbation due to viral infection are given in a dose of 50 mg a day for one week. If steroids don't work well enough, we combine them with aspirin desensitizations at a maintenance dose of 500 mg a day. Gastrointestinal side effects occur in 20% of the patients with a dose of 500 mg aspirin a day, in 46% with a mean dose of 1300 mg a day. The combined treatment of topical nasal steroids and aspirin-desensitization is effective in 65% of the patients with improvement in the symptoms of hyper-secretion, irritation and blockage, while 73% show improvement of polyps, hyposmia and anosmia. Endonasal endoscopic surgery of the ethmoids, turbinectoms and septoplasty should be done if necessary, especially in cases where conservative treatment fails. After surgery a further antiinflammatory treatment is absolutely necessary otherwise polyps reoccur in 90% of the cases after weeks or months. Unfortunately there is so far no curative treatment. New drugs like cytokine or leukotriene receptor antagonists give hope for better results in treatment of aspirin intolerance in the future.

Adrenal Cortex Hormones↗
PubMed1994

Protein-tyrosine phosphorylation regulates apoptosis in human eosinophils and neutrophils.

Early signaling events that control the process of programmed cell death are largely unknown. Tyrosine phosphorylation plays a major role in transmembrane signal transduction through most cell surface receptors. Granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine released by activated T cells, has been shown to increase tyrosine phosphorylation in several cells and to inhibit granulocyte cell death in vitro. In this study, we demonstrate that the effect of GM-CSF on granulocyte cell death can be blocked by the tyrosine kinase inhibitor genistein, suggesting that increases in tyrosine phosphorylation are essential to inhibit cell death. To analyze the role of tyrosine phosphorylation for the regulation of granulocyte cell death more precisely, we increased levels of tyrosine phosphorylation using the protein-tyrosine phosphatase inhibitor phenylarsine oxide (PAO). Similar to GM-CSF, treatment of the cells with PAO was followed by high increases in tyrosine phosphorylation and inhibition of programmed cell death in human eosinophils and neutrophils. Strikingly, at low concentrations of the inhibitor and low induction of tyrosine phosphorylation, acceleration of apoptosis was observed. Genistein and herbimycin A reversed the effects of PAO on tyrosine phosphorylation and granulocyte apoptosis. These results suggest that programmed eosinophil and neutrophil death is regulated by early events of signal transduction pathways such as tyrosine phosphorylation.

Apoptosis↗
PubMed1994

Functional platelet-activating factor receptors are expressed by monocytes and granulocytes but not by resting or activated T and B lymphocytes from normal individuals or patients with asthma.

Platelet-activating factor (PAF) may play a role in the regulation of immune responsiveness and is a potent mediator in asthmatic inflammation. However, as yet, the mechanisms whereby PAF mediates its pleiomorphic effects on immune cells have not been elucidated. Because PAF is a potent chemotactic factor for eosinophils, the presence of receptors for PAF (PAFR) on lymphocytes may provide a mechanism for the concurrent recruitment of both eosinophils and T lymphocytes into the airways of asthmatic patients. To address this issue, we have examined freshly isolated PBMC and granulocytic cells as well as various T and B lymphocyte lines with regards to PAFR expression and PAF-induced changes in intracellular calcium concentration. Using two-color immunofluorescence techniques and highly purified cell populations, it was not possible to detect surface PAFR protein or functional PAFR on resting and in vivo or in vitro activated T and B cells derived from nonallergic individuals or patients with allergic asthma. In addition, we were unable to detect PAFR mRNA, protein, or functional response to PAF in human or murine T cell lines. In contrast, we found functional PAFR in most B lymphoblastoid cell lines. Within the PBMC population, CD14+ cells respond to PAF. These results suggest that PAF does not interact directly with lymphocytes and thus that previous observations suggestive of such an interaction likely reflect the effects of PAF on monocytes. PAF-induced increases in intracellular calcium concentration were also detected in neutrophils and eosinophils, but were lower in granulocytes relative to the levels detected in monocytes.

Asthma↗
PubMed1994

Molecular characterization of hNRP, a cDNA encoding a human nucleosome-assembly-protein-I-related gene product involved in the induction of cell proliferation.

We have isolated from a human thymus cDNA library a cDNA clone encoding a potential protein with 54% amino acid similarity to that encoded by a previously identified cDNA for yeast nucleosome assembly protein I (NAP-I). The deduced amino acid sequence for this newly identified cDNA, designated hNRP (human NAP-related protein), contains a potential seven-residue nuclear localization motif, three clusters of highly acidic residues and other structural features found in various proteins implicated in chromatin formation. When expressed as a fusion protein in Escherichia coli, hNRP reacted specifically with a monoclonal antibody raised against human NAP-I. The hNRP transcript was detected in all tissues and cell lines studied, but levels were somewhat increased in rapidly proliferating cells. Moreover, levels of both hNRP mRNA and protein increased rapidly in cultured T-lymphocytes induced to proliferate by incubation with phorbol ester and ionomycin. Phorbol 12-myristate 13-acetate/ionomycin-induced increases in both hNRP mRNA and mitogenesis, as measured by thymidine incorporation, were markedly inhibited, however, in cells treated with an hNRP antisense oligonucleotide. These results demonstrate a correlation between induction of hNRP expression and mitogenesis and taken together with the structural similarities between hNRP and yeast NAP-I suggest that the hNRP gene product participates in DNA replication and thereby plays an important role in the process of cell proliferation.

Amino Acid Sequence↗
PubMed1994

High altitude climate therapy reduces peripheral blood T lymphocyte activation, eosinophilia, and bronchial obstruction in children with house-dust mite allergic asthma.

Asthma is a multifactorial disease of unknown etiology but often associated with atopy and inflammation. Previous studies in adult asthma have demonstrated the presence of activated T cells in blood, bronchoalveolar lavage (BAL) fluid, and bronchial tissue, and the relevance of their soluble products for eosinophil function. In view of these observations, it was hypothesized that similar pathogenetic mechanisms also occur in childhood asthma. In fact, peripheral blood T lymphocytes in 14 children with house-dust mite allergic asthma showed clear evidence of T cell activation as measured by the expression of CD25 and HLA-DR antigen. Without changing medication, significant reduction of the IL-2 receptor alpha-chain expression within the CD4+ lymphocyte population was observed after only 3 weeks of allergen avoidance. Within this time period, absolute and relative eosinophil numbers decreased to normal levels. After 5 weeks in an area of low house-dust mite exposure, lung function also presented evidence for clinical improvement of the asthmatic disease. These results indicate similar pathogenetic mechanisms in childhood and adult asthma. Furthermore, they suggest that allergen avoidance may contribute to the efficient therapy of asthma in patients with house-dust mite IgE-meditated allergy.

Adolescent↗
PubMed1994

Levels of soluble interleukin-2 receptor-alpha are elevated in serum and ascitic fluid from epithelial ovarian cancer patients.

OBJECTIVE: The purpose of the study was to determine whether ovarian cancer patients have activated lymphocytes as indicated by the presence of soluble interleukin-2 receptor-alpha and to compare soluble interleukin-2 receptor-alpha with other markers in ovarian cancer. STUDY DESIGN: Ascites and serum from patients with advanced active ovarian cancer was tested for the presence of elevated levels of soluble interleukin-2 receptor-alpha and compared with normal controls. Levels of soluble interleukin-2 receptor-alpha were also compared with levels of CA 125 and macrophage colony-stimulating factor in the same patients, to evaluate the correlation between different markers. RESULTS: Elevated levels of soluble interleukin-2 receptor-alpha were detected in 86 of 86 (100%) ascites samples and 67 of 85 (79%) serum samples from patients with advanced epithelial ovarian cancer. In contrast, only 12 of 25 (48%) benign ascites samples and one of 88 (1%) serum samples from controls had elevated levels. There was no obvious correlation between levels of soluble interleukin-2 receptor-alpha and levels of CA 125; however, levels of soluble interleukin-2 receptor-alpha did correlate with levels of macrophage colony-stimulating factor. Concurrent measurement of serum-soluble interleukin-2 alpha and CA 125 levels detected 100% of patients with epithelial ovarian cancer. CONCLUSION: The detection of elevated levels of soluble interleukin-2 receptor-alpha in serum and ascites indicates the presence of activated lymphocytes in patients with epithelial ovarian cancer. Ascites and serum levels of soluble interleukin-2 receptor-alpha are elevated in patients with advanced ovarian cancer and warrant assessment as a potential complementary marker to CA 125 for early detection of ovarian cancer and management of patients with advanced ovarian cancer.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1994

[Allergology in the year 2000].

As already today, the use of fully standardized allergens for specific allergen phenotyping will be essential also in the future. The determination of allergen-reactive patterns in patients will be performed with panels of tracer allergens being produced by molecular biology techniques. Such recombinant allergen proteins can in principal also be used for specific immunotherapy. Undesired biological properties of allergens can be removed by directed mutagenesis. Because recombinant allergens can bind IgE only selectively, T-cell activating fragments thereof may be employed. This may lead to fully artificial protein constructs consisting of immunogenic and allergy-suppressing parts. A different possible way is the therapeutic use of immunologically active proteins, such as monoclonal antibodies or soluble receptors, which suppress IL-4 and/or IgE synthesis. The accessibility of these proteins will lead to a better understanding of the mechanisms responsible for the development of allergy. At the end of this development one could conceive the construction of low molecular chemical agents, drugs in the classical sense, able to regulate IgE synthesis. Of highest significance will be the establishment of genetic markers for atopy and allergy. Such genes may not only indicate a genetic predisposition for the disease but also open an immense spectrum of new diagnostic and therapeutic applications in allergy.

Allergens↗