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Biomedical subjects

S Jung

Publications and source records attributed to S Jung.

At least 19 recordsLinked to original sources
PubMed1992

Prevention and therapy of experimental autoimmune neuritis by an antibody against T cell receptors-alpha/beta.

The mAb R73 directed to the TCR-alpha/beta of rat lymphocytes was tested for its therapeutic potential during the effector phase of experimental autoimmune neuritis (EAN) in Lewis rats. EAN can be actively induced by immunization with bovine peripheral nerve myelin, bovine P2 protein, or a peptide containing its neuritogenic epitope and serves as a model of the human Guilain-Barré syndrome. Adoptive transfer of activated P2-specific T lymphocytes also produces the monophasic disease (AT-EAN) characterized by inflammation and demyelination of peripheral nerves and highlights the central role of T lymphocytes in the pathogenesis of EAN. A single administration of the mAb R73 immediately after injection of activated P2-specific T line cells completely prevented the development of clinical and electrophysiologic signs of EAN in most animals and greatly alleviated the disease in the others. In further experiments mAb R73 was applied after the appearance of first clinical signs of EAN actively induced by immunization with a neuritogenic peptide or bovine peripheral nerve myelin. In both cases the anti-TCR-alpha/beta mAb reversed clinical signs of EAN and prevented the development of peripheral nerve dysfunction. In vivo and in vitro data suggest that impairment of Ag recognition and T cell function by occupancy of the TCR and R73-induced TCR-modulation rather than depletion of TCR-alpha/beta-bearing lymphocytes is the decisive mechanism underlying suppression of EAN that is apparent already within 48 h of the first R73 injection.

Animals↗
PubMed1992

Association of a heat-stable inhibitor protein with cyclic-3',5'-AMP-dependent protein kinase from the nematode Ascaris suum: purification and characterization of the inhibitor.

An inhibitor protein of the catalytic subunit of the cyclic 3',5'-AMP-dependent protein kinase from the nematode Ascaris suum was isolated and characterized. The molecular weight of the inhibitor was estimated as 28,000 by electrophoresis under denaturing conditions and as 30,000 by gel permeation chromatography on Superose 12. The Trypsin-labile inhibitor was resistant to short incubations (less than or equal to 5 min) at temperatures up to 95 degrees C and at pH 3. It affected the protein kinase from Ascaris and bovine heart with almost the same affinity, and inhibition was not relieved by the presence of cAMP and cGMP. However, the inhibition was antagonized by low concentrations of heparin. Unlike in mammalian tissues, the concentration of the inhibitor was sufficiently high to exert at least 90% inhibition of the protein kinase activity in Ascaris muscle. Therefore, the inhibitor may play a role in cellular regulation in the nematode.

Animals↗
PubMed1992

Inflammatory mediators in demyelinating disorders of the CNS and PNS.

Work in both experimental models and human disorders of the central and peripheral nervous system has delineated multiple effector mechanisms that operate to produce inflammatory demyelination. The role of various soluble inflammatory mediators generated and released by both blood-borne and resident cells in this process will be reviewed. Cytokines such as interleukin (IL)-1, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are pivotal in orchestrating immune and inflammatory cell-cell interactions and represent potentially noxious molecules to the myelin sheath, Schwann cells, and/or oligodendrocytes. Arachidonic acid metabolites, synthesized by and liberated from astrocytes, microglial cells and macrophages, are intimately involved in the inflammatory process by enhancing vascular permeability, providing chemotactic signals and modulating inflammatory cell activities. Reactive oxygen species can damage myelin by lipid peroxidation and may be cytotoxic to myelin-producing cells. They are released from macrophages and microglial cells in response to inflammatory cytokines. Activation of complement yields a number of inflammatory mediators and results in the assembly of the membrane attack complex that inserts into the myelin sheath-creating pores. Activated complement may contribute both to functional disturbance of neural impulse propagation, and to full-blown demyelination. Proteases, abundantly present at inflammatory foci, can degrade myelin. Vasoactive amines may play an important role in breaching of the blood-brain/blood-nerve barrier. The importance of nitric oxide metabolites in inflammatory demyelination merits investigation. A better understanding of the multiple effector mechanisms operating in inflammatory demyelination may help to devise more efficacious antigen non-specific therapy.

Animals↗
PubMed1992

Transient cellular expression of gamma-interferon in myelin-induced and T-cell line-mediated experimental autoimmune neuritis.

This study reports the cellular localization of gamma-interferon (gamma-IFN) in nerve roots during the course of experimental autoimmune neuritis induced either by active immunization (EAN) or adoptive transfer of P2-specific T-cells (AT-EAN). One micrometre thick cryosections of ventral roots of EAN and AT-EAN animals were labelled with the monoclonal antibodies DB-1 and DB-12 recognizing different epitopes of rat gamma-IFN. In EAN numerous gamma-IFN-positive cells were present before overt clinical signs and demyelination (days 11-13 after immunization). Concomitantly, raised gamma-IFN levels were measured in the serum of these animals. However, systemically increased gamma-IFN serum levels were not specific for a neuritogenic T-cell response. At subsequent stages when many axons were demyelinated (day 16 and later) gamma-IFN-positive cells had disappeared and gamma-IFN serum levels returned to normal value. gamma-Interferon positive cells could be identified as W3/13 positive T-cells and polymorphonuclear leukocytes. Additionally, a considerable number of ED1-positive macrophages showed gamma-IFN immunoreactivity. The majority of macrophages and all Schwann cells were gamma-IFN negative. Similar results were obtained in AT-EAN 4 d and 6 d following cell transfer. After nerve transection no gamma-IFN-positive cells were found in the distal stumps. The localization of gamma-IFN in nerve roots indicates an important role of this lymphokine in acute immune-mediated demyelination. gamma-Interferon most likely locally affects macrophage functions such as migration, major histocompatibility complex (MHC) class II antigen (Ia) expression, and production of cytotoxic molecules in nerves, and thereby contributes to myelin damage.

Animals↗
PubMed1992

Excitation of cutaneous sensory nerve endings in the rat by 4-aminopyridine and tetraethylammonium.

1. The effects of the potassium channel blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA) on cutaneous sensory nerve endings have been investigated with the use of an in vitro skin-nerve preparation from the rat. 2. Direct application of these compounds to the nerve endings, but not to the axons, induced continuous discharges in most A beta, A delta, and C fibers. There was no relationship between the fibers' responsiveness or the threshold concentration required to induce discharges and either the conduction velocity or sensory properties of the fibers. 3. The rate of induced discharges increased linearly with increasing concentrations of 4-AP. At threshold concentrations of 10(-6)-10(-5) M, low-frequency, irregular discharges developed; but at the highest concentration of 10(-3) M, a characteristic doublet or bursting discharges usually emerged. 4. During and after the induced discharges there did not appear to be an alteration in the sensitivity of the sensory nerve endings to mechanical or thermal stimuli. 5. It is concluded that the induced activity arises from an action of these potassium channel blockers at or near the action potential generator region at the nerve endings.

4-Aminopyridine↗
PubMed1991

Human T lymphocytes recognize a peptide of single point-mutated, oncogenic ras proteins.

P21ras proteins are thought to play an important role in cell proliferation and differentiation. Single nucleotide mutations in the encoding cellular proto-oncogenes often result in p21ras proteins with transforming activity. Such activated ras oncogenes have been demonstrated in a variety of human malignancies and also in preneoplastic changes. Using a synthetic peptide corresponding to amino acids 5-16 of mutated p21ras proteins with an exchange of the normal glycine at position 12 by valine, it is shown here that human CD4+ T cells specifically recognize the mutated protein sequence and can be generated as antigen-specific T lymphocyte lines. The fact that these T lines did not crossreact to the sequence of normal p21ras proteins offers new perspectives for specific immunotherapy of human malignancies and even precancerous lesions.

Amino Acid Sequence↗
PubMed1991

Acetylcholine receptor-specific T-lymphocyte clones in the normal human immune repertoire: target epitopes, HLA restriction, and membrane phenotypes.

Potentially autoimmune T-lymphocyte lines specific for the nicotinic acetylcholine receptor of the neuromuscular junction have been isolated previously from patients with myasthenia gravis. We report on the isolation and expansion of T cells specific for the acetylcholine receptor of Torpedo californica or for a recombinant mammalian acetylcholine receptor alpha chain peptide (X4), from the peripheral blood of 11 healthy donors. Two major T-cell epitopes, located between amino acid positions 44-104 and 141-172, were identified using a panel of overlapping mammalian alpha chain fusion proteins. Most T lines recognized the acetylcholine receptor epitopes in the molecular context of HLA-DR molecules. Unexpectedly, all the T. californica acetylcholine receptor-specific T lines obtained from one DR4 (DRw53), DQw3 donor and two DR4, w8 (DRw53), DQw3 donors were restricted by DRw53 product(s). Using DR gene-transfected L cells as antigen presenters, in 4 lines, a close relationship between the recognized epitope and the restricting DR element was revealed. The membrane phenotype of the T. californica acetylcholine receptor-and X4-specific T lines was predominantly CD4+CD8-, with some CD4+CD8+ components. It did not significantly differ from that of control, tuberculin purified protein derivate-specific T lines raised from the same donors. These findings are in harmony with previous ones demonstrating the presence of potentially autoimmune T-lymphocyte clones within normal immune repertoires.

Antigens, CD↗
PubMed1991

T cell vaccination does not induce resistance to experimental autoimmune neuritis.

The effectiveness of T cell vaccination was analyzed in experimental autoimmune neuritis (EAN) that can be induced by immunization with bovine P2 protein or a peptide representing the amino acids 53-78 of P2 (P2 53-78). Lewis rats were vaccinated with glutaraldehyde-fixed lymph node cells which had been primed in vivo with P2 protein or P2 53-78 and had been activated in vitro with concanavalin A. Vaccinated animals were not protected from EAN induced by immunization with P2 protein in complete Freund's adjuvant (CFA). In a second set of experiments Lewis rats were vaccinated with irradiated or fixed P2-specific T cell lines of different specificity and neuritogenicity and were subsequently challenged with P2 53-78 in CFA. Likewise, severity of P2 53-78-induced EAN was not different between naive and T line-vaccinated groups. In spleens of vaccinated animals a substantial suppressive activity was demonstrated which was positively correlated with a weak anti-ergotypic response of these spleen cells. The fact that development of actively induced EAN was not prevented or even mitigated by T cell vaccination, in spite of an apparent vaccination-induced response to and on T lymphocytes, suggests that protection from disease is not readily induced in every autoimmune disease model.

Animals↗
PubMed1991

Monoamine turnover in the brain of mice during development of tolerance to the anticonvulsant effect of clonazepam.

Mice were treated for 14 days with clonazepam, 0.5 mg/kg i.p. twice daily, during which time partial tolerance to the anticonvulsant effect against pentetrazole developed. The development of tolerance was paralleled by a reduced turnover of noradrenaline in the whole brain, and of dopamine in the midbrain. The turnover of 5-HT was increased during the first week of treatment, but decreased thereafter. These changes in monoamine turnover, which are thought to be GABA-mediated, are consistent with an increased seizure susceptibility, and may contribute to the development of tolerance to the anticonvulsant effect of benzodiazepines.

Animals↗
PubMed1991

Nicotinamide ethers: novel inhibitors of calcium-independent phosphodiesterase and [3H]rolipram binding.

The synthesis and biological properties of a series of nicotinamide ethers are described. These compounds, structurally novel calcium-independent phosphodiesterase inhibitors, also inhibit the binding of [3H]rolipram to rat brain membranes and reverse reserpine-induced hypothermia in the mouse. Several compounds exhibited potent in vivo activity comparable to the standard agent, rolipram.

Animals↗
PubMed1991

Calcium-independent phosphodiesterase inhibitors as putative antidepressants: [3-(bicycloalkyloxy)-4-methoxyphenyl]-2-imidazolidinones.

The synthesis and biological properties of a novel series of selective calcium-independent phosphodiesterase inhibitors are described. These compounds also inhibit the specific binding of [3H]rolipram to rat brain membranes and exhibit efficacy in preclinical models of antidepressant activity in mice, such as reducing immobility in the forced-swim test and reversing reserpine-induced hypothermia. Imidazolidinones 4 and 16 were found to be the most potent compounds studied.

Animals↗
PubMed1990

Prophage lambda libraries for isolating cDNA clones by functional screening.

Isolation of cDNA clones from lambda gt11 phage libraries by functional screening is limited by the low amount of lacZ-cDNA-encoded fusion protein synthesized in an isolated phage plaque. The amount of specific cDNA-encoded protein can be significantly enhanced by expression in bacterial colonies rather than phage plaques. Escherichia coli was lysogenized with a lambda gt11 cDNA expression library from Dictyostelium discoideum. Bacteria were selected for the presence of the lambda gt11 prophage by elimination of nonlysogenic parental cells with a lambda cI phage. The usefulness of the lysogen library was demonstrated by immuno-screening and functional screening with two different radiolabeled ligands. cDNA clones encoding a well-characterized D. discoideum protein, the regulatory subunit of the cAMP-dependent protein kinase, were isolated by screening the lysogen library with antibodies. Clones encoding this protein could also be identified by functional screening with [3H]cAMP, demonstrating that the limit of detection of positive clones by ligand screening is at least an order of magnitude lower for the lysogen library than for the corresponding phage library. We have subsequently used the lysogen library to isolate cDNA clones encoding calmodulin-binding protein(s) from D. discoideum by functional screening with [125I]calmodulin. For these clones, screening of the corresponding phage library had previously been found unsuccessful.

Bacteriophage lambda↗
PubMed1990

Slow tight-binding inhibition of prolyl endopeptidase by benzyloxycarbonyl-prolyl-prolinal.

Prolyl endopeptidase is a serine proteinase that specifically cleaves peptides on the carboxy side of proline residues. Wilk & Orlowski [(1983) J. Neurochem. 41, 69-75] have shown that benzyloxycarbonyl-prolyl-prolinal (Z-prolyl-prolinal) is a potent inhibitor of prolyl endopeptidase. We show that Z-prolyl-prolinal is a slow-binding inhibitor of mouse brain prolyl endopeptidase with Ki 0.35 +/- 0.05 nM. Kinetic analysis indicates that the mechanism is a simple, but slow, reversible equilibrium between free and bound enzyme (E + I in equilibrium EI) with rate constants for association (kon) and dissociation (koff) of 1.6 X 10(5) M-1.s-1 and approx. 4 X 10(-5) s-1 respectively. Slow-binding inhibition is dependent on the presence of the aldehyde group since the alcohol (Z-prolyl-prolinol) is a rapid and 50,000-fold poorer inhibitor (Ki 19 microM). Prolyl endopeptidase from human brain is also inhibited by Z-prolyl-prolinal with kinetics similar to those of the mouse brain enzyme.

Animals↗
PubMed1990

Substrate specificity for myelin basic protein-specific protein methylase I.

The substrate specificity of bovine brain myelin basic protein (MBP)-specific protein methylase I (S-adenosyl-L-methionine:protein-L-arginine N-methyltransferase, EC 2.1.1.23), which methylates arginine residues of protein, has been studied using various MBPs, several synthetic peptides and heterogeneous nuclear ribonucleoprotein complex protein (hnRNP). (1) Among MBPs from different species of brain, the carp MBP was found to be the best substrate for MBP-specific protein methylase I. This high degree of methyl acceptability is most likely due to the fact that carp MBP is not in vivo methylated at the arginine residue (Deibler, G.E. and Martenson, R.E. (1973) J. Biol. Chem. 248, 2387-2391) and that the methylatable amino acid sequence is present in this protein. (2) In order to study the minimum chain length of MBP polypeptide which functions as the methyl acceptor, several synthetic polypeptides whose sequences are identical to the region surrounding the residue 107 of bovine MBP (the in vivo methylation site) were synthesized. It was found that the hexapeptide, Gly-Lys-Gly-Arg-Gly-Leu (corresponding to residues 104-109 of bovine MBP), was the shortest methyl accepting peptide, while the tetrapeptide, Gly-Arg-Gly-Leu (corresponding to residues 106-109) was inactive as a substrate. (3) hnRNP protein is known to contain methylarginine at residue 193 (Williams, K.R., Stone, K.L., LoPresti, M.B., Merrill, B.M. and Plank, S.R. (1985) Proc. Natl. Acad. Sci. USA 82, 5666-5670) which is post-translationally modified. Thus, the RNP protein overproduced in Escherichia coli and therefore did not contain methylarginine was examined for its methyl acceptability. It was found that neither MBP-specific nor histone-specific protein methylase I could methylate this methylarginine-less RNP protein. This suggests a possible existence of a distinct protein methylase I specific for this nuclear protein.

Amino Acid Sequence↗
PubMed1990

Carrageenan inflammation increases bradykinin sensitivity of rat cutaneous nociceptors.

The present study examined the hypothesis that the sensitivity of polymodal nociceptors to bradykinin (BK) might be increased in inflamed tissue. Inflammation was induced in the rat dorsal hindpaw skin by subcutaneous injection of blue stained carrageenan. Three hours later skin and saphenous nerve were excised and the chemical sensitivity of mechano-heat-sensitive C- and A delta fibres was examined in vitro using repeated superfusion of the receptive fields with 10(-5) M BK. Only units within and at the border of the inflamed area showed signs of sensitization, in the form of ongoing activity and lower thresholds to heat stimuli. No sensitization to mechanical (von Frey) stimulation occurred. The incidence of BK responsiveness was significantly higher and the tachyphylaxis to repeated BK application was smaller inside the inflamed skin than outside or in unconditioned skin. Thus, more nociceptive afferents would be driven more effectively than in normal skin, supporting the particular role of BK in inflammatory pain.

Action Potentials↗
PubMed1990

Susceptibility and resistance of human autoimmune T cell activation to the immunoregulatory effects of transforming growth factor (TGF) beta 1, beta 2, and beta 1.2.

The transforming growth factors type beta (TGF-beta) regulate immune responses by suppressing a variety of leukocyte functions. Using a panel of human autoimmune T cell lines specific for the acetylcholine receptor (AchR) we investigated the immunoregulatory effects of TGF-beta 1, TGF-beta 2, and TGF-beta 1.2. The cytokines have identical effects inhibiting activation of most T line cells and the activation-dependent changes in interleukin-2 (IL-2) receptor and T cell receptor expression. IL-2-dependent growth was not modulated by TGF-beta. However, autoimmune T cell lines specific for AchR differ in their susceptibility to TGF-beta and some are completely refractory. Resistance of autoimmune T cell activation to immunosuppressive cytokines might be an element in the development of chronic autoimmune disease.

Antigens, Surface↗
PubMed1986

[Blood fibronectin changes in various neoplasms].

In 85 patients presenting with various cancers, changes in the frequencies of plasma fibronectin and of the carcino-embryonic antigen (CEA) were compared and the results were correlated with the degree of extension. Forty-six percent of patients with mammary adenocarcinoma had plasma fibronectin values higher than the age-related limit range, but only 18% had an increase in CEA. In patients with secondary metastases, the highest values were significantly different from those found in controls. In these cases, fibronectin was present in abnormal concentrations in more than 80% of the patients, and CEA in 50%. Positive fibronectin values were less frequent in other cancers, except those of the genital tract. Neither fibronectin nor CEA are organ-specific, yet these two tumoral markers differ in the frequency with which they appear, notably in patients with mammary carcinoma.

Adult↗