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Biomedical subjects

M Stangel

Publications and source records attributed to M Stangel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins ("IVIg").

High-dose intravenous immunoglobulin (IVIg) treatment has become a promising immune therapy that can modulate the immune system at several levels, including the complement cascade. In relation to inflammatory demyelinating disease, there is some clinical evidence for the suppression of disease activity by IVIg, while a role in promoting remyelination after experimental myelin damage has been described. Antibody and complement deposition have been implicated in the immune attack in some cases of multiple sclerosis (MS), and to investigate the mechanisms of action of IVIg, we studied the effect of IVIg using the model of complement-mediated cell injury on oligodendroglia in vitro. There was no effect on direct complement lysis of the oligodendroglial cell line CG4, but antibody-dependent complement damage was inhibited in a dose-dependent manner by IVIg. These results were confirmed with primary cultures of oligodendrocyte precursor cells (OPC) and oligodendrocytes. The addition of excess C1, C3, and C4 did not influence the inhibitory effect of IVIg, implying that binding of these complement components does not play a role, in contrast to other experimental models of complement damage. F(ab')2 immunoglobulin fragments were at least partially responsible for the effect. We conclude that IVIg may be protective in antibody-mediated complement injury of oligodendrocytes and their progenitors, and that this effect is likely to be mediated via antibody binding, rather than interference with complement activation. Inhibition of inflammatory mechanisms, as opposed to a direct effect on remyelinating cells, may underlie the role of IVIg in promoting myelin repair in experimental models.

Animals↗
PubMed2000

Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis.

Currently there is no treatment available to improve a stable deficit in multiple sclerosis. It was shown in animal models that intravenous immunoglobulins (IVIg) can enhance central nervous remyelination, and the first open trials were promising. We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with multiple sclerosis with a stable clinical deficit. The primary outcome parameter was the change in central motor conduction time as an indirect measure of central myelination. Secondary outcome parameters were neurological examinations including the expanded disability status scale (EDSS), neurological rating scale (NRS), and manual muscle testing (MMT). Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks. There was no difference in the central motor conduction times measured before and 6 weeks after each treatment. Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo. In conclusion, our data do not support a role for IVIg in the remyelination of stable multiple sclerosis lesions as measured by central conduction time. The importance of the small clinical benefit is currently not clear.

Adult↗
PubMed1999

Polyclonal immunoglobulins for intravenous use do not influence the behaviour of cultured oligodendrocytes.

Treatment studies in multiple sclerosis and the experimental murine model of Theiler's virus encephalomyelitis have suggested that intravenous immunoglobulins (IVIg) promote central nervous system remyelination. It is not clear if this results from a direct effect on myelinating oligodendroglial cells, or from suppression of the immune response permitting better endogenous repair. We systematically explored the effects of IVIg on various aspects of oligodendrocyte precursor cell (OPC) behaviour in vitro. Neither proliferation, differentiation nor migration of OPC was affected by IVIg. These results argue against a direct effect of IVIg on remyelination and are in favour of an indirect yet not clearly defined mechanism that supports remyelination.

Animals↗
PubMed1999

Mechanisms of high-dose intravenous immunoglobulins in demyelinating diseases.

Administration of high-dose intravenous immunoglobulins has become one of the most successful new treatment regimens for demyelinating diseases. In a decade of molecular medicine, it came as a surprise that a natural blood product would prove effective in several disorders, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and, probably, multiple sclerosis. Many experimental studies, both in vivo and in vitro, have shown that intravenous immunoglobulins can interfere with the immune system at several levels. In addition, intravenous immunoglobulins may promote remyelination in demyelinating disease associated with viral infections. At present, no single mode of action has been identified as the crucial mechanism, which leads us to suggest that multiple effects may act in concert.

Antibodies, Anti-Idiotypic↗
PubMed1998

Intravenous immunoglobulin treatment of neurological autoimmune diseases.

Intravenous immunoglobulin (IVIg) has been widely used in neurological diseases during the last decade. The current indications of IVIg in neurological diseases are reviewed and discussed on the basis of the available experimental data and clinical trials. Compared to other immunomodulating treatments used in neurological diseases, IVIg has only few side effects with a small risk of transmission of infectious agents. Good clinical evidence for the effectiveness is available for Guillain-Barré-Syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. In conditions like myasthenia gravis and myositis favourable effects of IVIg were reported, but future studies have to be awaited. For all other neurological conditions where IVIg has been administered, there is currently no support for the use of IVIg other than in controlled trials. In conclusion, IVIg is a promising immunomodulary therapy that has been shown to be effective in some neurological autoimmune diseases. Routine use in neurological practice should be restricted to diseases for which a positive effect has been proven in controlled trials. For all other conditions no definite recommendations can presently be made.

Autoimmune Diseases↗
PubMed1998

[Septo-optic dysplasia (de Morsier syndrome)].

Septo-optic dysplasia (or de Morsier syndrome) is a congenital disorder characterised by anomalies in cerebral midline structures, optic nerve hypoplasia, and hormonal deficiencies. Diagnosis should be made early, due to the possibility of treating the hormonal disturbances. We describe here a case with decreased visual acuity, one-sided hemianopia, nystagmus und agenesis of the septum pellucidum and discuss the heterogeneous appearance of this syndrome. There are two theories regarding its pathogenesis. The first postulates simultaneous damage to both cerebral structures and optic nerve development around the 6th week of gestation, while the other favours secondary degeneration of optic nerve fibres due to a cerebral lesion.

Adolescent↗
PubMed1997

Cerebellar atrophy with basilar artery occlusion.

Small and large vessel occlusive disease leading to chronic cerebral ischemia and brain atrophy is a concept originating in the last century. The modern notion of acute brain infarct, however, appears to have eclipsed the idea of chronic hypoperfusion as an important factor in ischemic cerebral damage. We present a patient history featuring recurrent episodes of acute posterior circulation infratentorial ischemia in addition to a progressive cerebellar syndrome over a course of several years. Laboratory work-up including cerebral angiography, repeated CT and MR scanning revealed basilar artery occlusion, a pontine infarct and a subsequently developing cerebellar atrophy without signs of cerebellar infarction. Findings indicating causes of cerebellar atrophy other than ischemia could not be elicited. We offer the hypothesis that basilar artery occlusion, inducing subsequent chronic ischemia, is the most likely cause of the cerebellar atrophy observed in our case.

Adult↗
PubMed1997

Apoptosis of myelin-reactive T cells induced by reactive oxygen and nitrogen intermediates in vitro.

Apoptosis is a major mechanism of T cell elimination during ontogeny and tolerance induction as well as in autoimmunity. To assess the possible involvement of reactive oxygen and nitrogen intermediates (ROI and NO.) in T-cell apoptosis during autoimmune demyelination we investigated the effects of H2O2 and NO. in vitro on activated autoreactive CD4+ T cell lines capable of transferring experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). For detection and quantitation of apoptotic cells, DNA fragmentation was assessed by in situ tailing with fluorescein-ddUTP and subsequent flow cytometric analysis. H2O2 applied directly to the cell cultures for 6 to 18 hr at concentrations of 10 to 300 microM and ROI released by combination of hypoxanthine and xanthine oxidase (HX/XO) caused apoptosis in a dose-dependent manner in 13-33% of T cells of neuritogenic and encephalitogenic T cell lines. Apoptosis induction could be suppressed by the H2O2-neutralizing enzyme catalase. NO. released by the penicillamine derivative SNAP induced apoptosis to a similar extent as ROI. Maximum values were 38% in an encephalitogenic V beta 8.2-T cell receptor-bearing T cell line and 26% in a neuritogenic T cell line. T cell lines with specificity to ovalbumin revealed slightly lower susceptibility to apoptosis induction by all three kinds of trigger, which is, however, most probably not due to the different antigen specificity, but rather a result of fewer in vitro restimulation cycles of these cells. In neuritogenic cells high-dose (100 units/ml) exogenous interleukin-2 (IL-2) prevents H2O2-induced apoptosis. In conclusion, macrophage-derived reactive oxygen and nitrogen intermediates have the potency to limit inflammatory demyelination by elimination of autoreactive and bystander T cells via apoptotic cell death, and IL-2 is a rescue factor.

Animals↗
PubMed1997

Side effects of high-dose intravenous immunoglobulins.

Intravenous immunoglobulins (IVIgs) are used increasingly as therapy for neuroimmunologic and other autoimmune diseases. With broader use, the number of reported side effects also is growing. Here we review the literature on adverse reactions reported after administration of i.v.Igs. Despite a few recent reports about a high frequency of complications of IVIgs, by and large they can be considered as safe. Mild and self-limited side effects may occur, but severe complications are rare and often associated with other risk factors for these complications. A careful screening for preexisting illnesses and monitoring of some laboratory parameters can minimize the risks of IVIg therapy.

Dose-Response Relationship, Drug↗
PubMed1996

[A quickly reversible occlusion in the vertebrobasilar circulatory bed: often unrecognized?].

HISTORY AND FINDINGS: A 29-year-old man presented in another hospital because of discoordination of all extremities with sudden onset. After fast reversal of the symptoms, he was discharged without a clear diagnosis. Because of remaining discrete dysarthria, computed tomography and magnetic resonance imaging were performed which demonstrated bilateral cerebellar infarcts. The cause was assumed to be a transient embolic occlusion of the distal basilar artery. TREATMENT AND COURSE: Intravenous heparin was started to prevent further occlusions. Because no source for emboli or other causes were found, the patient was discharged after 14 days on acetylic acid (250 mg/d) as secondary prevention therapy. CONCLUSIONS: A vascular or neurological cause is often not considered when neurological symptoms are quickly reversible after a transient occlusion of the basilar artery. In these cases, the suspected diagnoses of psychiatric illness, alcohol abuse, drug intoxication, infection or myocardial infarction do not lead to the necessary investigations. Thus, a potentially life-threatening situation may be disregarded.

Adult↗
PubMed1996

H2O2 and nitric oxide-mediated oxidative stress induce apoptosis in rat skeletal muscle myoblasts.

In many degenerative and metabolic muscle diseases cells die without a marked inflammatory response. A potential mechanism how this could be accomplished is apoptotic cell death. Since there are no data available about apoptosis in cells of myogenic origin, we examined rat skeletal myoblasts for their potential to undergo apoptosis when exposed to reactive oxygen intermediates and nitric oxide. We observed morphologic changes typical for apoptotic cell death, and DNA fragmentation was confirmed by gel electrophoresis and molecular labeling assays. With these methods we could show that both reactive oxygen intermediates and nitric oxide can induce apoptosis in myoblasts in a dose-dependent manner. These results are discussed with regard to possible implications on the pathophysiology of various muscle diseases.

Animals↗
PubMed1995

Structural analysis of the rat T-cell receptor Tcra V4 gene family.

The rat Tcra V gene locus is only poorly characterized, although rats are widely used in a variety of T-cell-mediated experimental animal models. Recently, we described the first monoclonal antibody, G99, directed against a rat Tcra V4 segment. We examined cDNA transcripts of G99-positively sorted T cells and show that the monoclonal antibody G99 most likely recognizes at least two members of the Tcra V4 family. Moreover, we analyzed the genomic repertoire of this VA family and report 15 novel Tcra V4 DNA sequences. Based on sequence and Southern blot analysis, the Tcra V4 family could be divided into four subgroups, which were also detected in mice. These findings corroborate previous findings of a similar genetic organization of the Tcra V loci in both species.

Amino Acid Sequence↗
PubMed1994

Bacterial expression of a soluble T-cell receptor alpha chain.

A bacterial expression system was used to express the complete extracellular domain of a rat T-cell receptor alpha-chain, including variable-, joining and constant regions. By introduction of a His-tail at the C-terminus, a simple and rapid purification protocol utilizing Ni(+)-chelating chromatography was applied, with renaturation of the protein while bound to the matrix. This method produced large amounts of soluble protein, which provide a source for T-cell receptor analysis and further studies on T cell function.

Amino Acid Sequence↗
PubMed1990

Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis.

Using detailed functional studies on 24 human transferrin receptor mutants, we identified YXRF as the internalization sequence. Provided that at least 7 residues separate this tetrapeptide from the transmembrane region, changing the tetrapeptide position within the TR cytoplasmic domain does not reduce internalization activity. Thus, any conformational determinant for internalization must be localized to the YXRF sequence. Twenty-eight tetrapeptide analogs of YXRF, found by an unbiased search of all known three-dimensional protein structures, significantly favored tight turns similar to a type I turn. Of the ten tetrapeptides most closely related to YXRF, eight were surface exposed and had tight-turn conformations, as were four of five tetrapeptides with sequences related to the low density lipoprotein receptor internalization motif, NPXY. The internalization sequences of both receptors contain aromatic residues with intervening hydrogen-bonding residues. Thus, two distinct internalization sequences favor a common structural chemistry and implicate an exposed tight turn as the recognition motif for high efficiency endocytosis.

Amino Acid Sequence↗
PubMed1989

[The primary structure of crystallizable monoclonal immunoglobulin IgG1 Kol. II. Amino acid sequence of the L-chain, gamma-type, subgroup I].

The immunoglobulin Kol was the first intact antibody molecule which was characterized by high-resolution X-ray crystallography. Furthermore the complete amino-acid sequence of the heavy (H)-chain is known. Here we report the complete amino-acid sequence of the light (L)-chain of the monoclonal immunoglobulin Kol (IgG1). The polypeptide has an Mr of 22,781, consists of 216 amino acids and due to its structure is of the lambda-type. With the characteristic amino acids threonine, asparagine, threonine, glycine and lysine in positions 101, 114, 116, 154, and 165, respectively the Kol L-chain is of the Mcg isotype. With the proteins Mcg, Mot, Bur, Loc and Mem six myeloma-derived amino-acid sequences of the same isotype are known. The amino-acid sequence of the N-terminal variable part is characteristic of subgroup 1. This contribution completes the primary structure of IgG1 Kol.

Alkylation↗