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Biomedical subjects

U Traugott

Publications and source records attributed to U Traugott.

At least 19 recordsLinked to original sources
PubMed1992

A prospective study of depression and immune dysregulation in multiple sclerosis.

This study examined psychologic distress and immune function in patients with chronic-progressive multiple sclerosis participating in a placebo-control trial of cyclosporine. Immune measures included percentages and absolute numbers of CD2+, CD4+, CD8+, Leu-11-b+, HLA-DR (IA+), and transferrin-receptor-positive cells, which were evaluated by immunofluorescence using monoclonal antibodies. Distress was measured with self-report scales. The Expanded Disability Status Scale assessed neurologic disability. Subjects were followed up for 2 years, and their high-depressed and low-depressed times were compared. Times of greater depression were associated with lower CD8+ cell numbers and CD8+%, and a higher CD4/CD8 ratio. CD4+ cell numbers and percent were also higher when subjects were depressed, but only in the placebo group. There were no differences in Expanded Disability Status Scale when subjects were more depressed. Evaluation of a single subject revealed that Ia+ and transferrin-receptor-positive lymphocytes increased 3 months before distress increased. It was concluded that distress is associated with immune dysregulation in multiple sclerosis, although the mechanisms of this association have yet to be delineated.

Adult↗
PubMed1992

On the immunopathology of multiple sclerosis lesions.

Active chronic multiple sclerosis (MS) lesions contain numerous T-200 and leukocyte function associated antigen (LFA)-1-positive infiltrating cells. Macrophages at the lesion edge are stained for immunoglobulins (Ig), Class I and Class II major histocompatibility complex (MHC) antigens, for interferon (IFN)-alpha and for the beta-2 integrin adhesion molecule gp 150/95. In the periplaque area, numerous CD2, CD4, and CD8 positive T cells and cells reactive for the CD45RO phenotype of memory cells and for gamma/delta T cell receptors are located between MHC-positive glial cells. White matter at the edge is diffusely stained for intercellular adhesion molecule (ICAM)-1 and LFA-3. Remote from lesions, labeling for Class II MHC, ICAM-1 and LFA-3 was enhanced on some endothelial and glial cells. These findings indicate that adhesion molecules are involved in the formation and possibly also in the reactivation of MS lesions.

Antigens, CD↗
PubMed1991

Phase I and pharmacokinetic study of D-verapamil and doxorubicin.

The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

[Reversal of multidrug resistance with (R)-verapamil in vitro and in vivo].

The clinical use of racemic (R/S)-verapamil (CAS 52-53-9) as resistance modifier is limited because of the cardiovascular activity of the substance. The stereoisomer (R)-verapamil shows significant less cardiovascular activity. Therefore we tested the resistance modifying abilities of (R)-verapamil and (R/S)-verapamil in murine multidrug-resistant L 1210 ascites-tumor-cells in vitro and in vivo. The present results demonstrate, that the (R)-isomer has the same resistance modifying effects as racemic verapamil. Both modifying substances have no effects in the parental (sensitive) and cytosine-arabinoside resistant L 1210 ascites-tumor-cells. Thus, (R/S)-verapamil and (R)-verapamil show their resistance modifying abilities only in multidrug-resistant tumor-cells.

Animals↗
PubMed1990

Increase in anti-astrocyte antibodies in the serum of guinea pigs during active stages of experimental autoimmune encephalomyelitis.

From previous studies on the induction and treatment of experimental autoimmune encephalomyelitis (EAE) in guinea pigs and mice, antibodies have been implicated during both demyelination and remyelination. In the present study, sera from guinea pigs with acute, chronic and myelin basic protein/galactocerebroside (MBP/GC)-treated chronic EAE were evaluated for the presence of anti-glial cell antibodies by immunocytochemical techniques. Antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The majority of sera from acute and chronic active EAE animals displayed intense labelling of astrocytes and only weak staining of oligodendrocytes when tested on sections of normal guinea pig brain tissue. In contrast, sera from animals with chronic EAE treated with MBP/GC gave strong labelling of oligodendrocytes and only minor staining of astrocytes. By immunoblotting, astrocyte staining was shown to be due to the presence of antiglial fibrillary acidic protein (GFAP) antibodies. The intense oligodendrocyte staining observed in sections reacted with sera from MBP/GC-treated guinea pigs corresponded well with high titers of serum anti-GC and anti-MBP antibodies measured by an ELISA. It was concluded that the presence of antibodies against astrocytes was possibly related to astrocytic antigens within the disease-inducing emulsion, at least during the initial phases of EAE, and not to their release from the central nervous system of affected animals.

Animals↗
PubMed1989

Tropical spastic paraparesis: a model of virus-induced, cytotoxic T-cell-mediated demyelination?

Tropical spastic paraparesis is a neurological disorder that is most commonly seen in certain tropical (mainly Caribbean) areas and that presents as a progressive spastic paraparesis and urinary dysfunction. Recent studies have revealed an association between tropical spastic paraparesis and human T-cell lymphotropic virus type I (HTLV-I) infection. We report the results of a detailed morphological and immunocytochemical study of a patient with tropical spastic paraparesis. Lesions were restricted to the spinal cord and optic nerve, where demyelination, inflammation, and fiber loss were common features. Lymphocytes were seen closely applied to nerve fibers within which were changes resembling those seen in myelinated central nervous system cultures exposed to cytokines. Immunocytochemically, HTLV-I p19 core protein and a predominance of CD8+ (suppressor/cytotoxic) T cells and expression of class I major histocompatibility antigen were demonstrated in spinal cord lesions. It is postulated that cytotoxic T cells, either directly or via cytokines, induce lysis of the myelin sheath and subsequently the axon, resulting in a mixed picture of demyelination and axonal loss with secondary tractal degeneration. Despite this destruction, extensive remyelination was evident within affected areas of spinal cord.

Female↗
PubMed1989

Detailed analysis of early immunopathologic events during lesion formation in acute experimental autoimmune encephalomyelitis.

To investigate early immunopathologic events, SJL/J mice were challenged for acute experimental autoimmune encephalomyelitis (EAE) and sampled between 12 hr and 14 days postinoculation (PI). Complete Freund's adjuvant (CFA)-inoculated mice served as controls. T cells, T cell subsets, Class II major histocompatibility (MHC) antigen (Ia)-positive and immunoglobulin (Ig)-positive cells, albumin and Ig deposits, and myelin antigens were localized in frozen sections of central nervous system (CNS) and non-CNS tissue (heart, liver, kidney) by immunocytochemical techniques. In both experimental groups, a few Ia-positive endothelial cells and low-grade diffuse infiltration by T cells, T cell subsets, and Ia+ and Ig+ cells were seen from 12 hr PI onward in CNS and non-CNS tissue. Only in acute EAE but not in CFA-challenged mice were these early changes followed at 10 days PI by extensive inflammation which was restricted to the CNS and was accompanied by Ia-positive astrocytes. Thus, in acute EAE, immunopathologic changes appear to develop in two stages. During the early low-grade generalized phase, recirculation of lymphocytes is moderately enhanced while during the late phase, extensive immunopathology is focused upon the target organ, the CNS.

Acute Disease↗
PubMed1988

Multiple sclerosis: involvement of interferons in lesion pathogenesis.

To investigate a possible role of interferons (IFNs) in lesion pathogenesis, central nervous system tissue from multiple sclerosis patients and control subjects was stained by immunocytochemical techniques in combination with monoclonal antibodies or polyclonal antisera for the demonstration of IFN-alpha, IFN-beta, and IFN-gamma. The results were correlated to lesion activity, to the presence of class I and class II major histocompatibility antigen-positive astrocytes, and to the composition of cellular infiltrates. IFNs were detectable in active but not in inactive chronic multiple sclerosis lesions. In acute multiple sclerosis plaques, all three types of IFN were widely distributed on glial elements and infiltrating cells. In active chronic multiple sclerosis, labeling of cells for IFN-alpha, IFN-beta, and IFN-gamma was most pronounced at the lesion edge and displayed distinct distribution patterns. Overall, IFN-gamma was more common than IFN-alpha and IFN-beta and was predominantly found on astrocytes. IFN-alpha was detectable mainly on macrophages. Distribution of IFN-beta partially overlapped with that of IFN-gamma and IFN-alpha, in that it was present on some astrocytes and on some macrophages. IFNs were rare in normal white matter remote from lesions and in the gliotic lesion center. Ia antigen and human leukocyte antigen ABC on astrocytes were distributed similarly to IFN-gamma and IFN-beta, respectively. These findings indicate that IFN-gamma may play a role in active lesion growth in multiple sclerosis, whereas IFN-alpha and IFN-beta may exert some local immunosuppressive effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Interferon-gamma and Ia antigen are present on astrocytes in active chronic multiple sclerosis lesions.

Using immunocytochemical techniques, presence of interferon (IFN)-gamma, IFN-alpha and Class II major histocompatibility (MHC) antigen (HLA-DR, Ia) was evaluated in active central nervous system (CNS) lesions of 11 patients with chronic multiple sclerosis (MS) and the findings were correlated with a detailed analysis of inflammatory cells. Both IFN-gamma and Ia antigen were detectable on astrocytes at the edge of active chronic MS lesions and in the adjacent normal-appearing white matter, where CD4+ (helper/inducer) T cells and interleukin-2 receptor (IL-2R)-positive cells were also found. IFN-alpha was predominantly seen on Ia-positive macrophages and not on astrocytes. Astroglia in the inactive lesion center and in normal CNS parenchyma were unreactive for both types of IFN and Ia antigen. These findings suggested that similar to the situation in vitro, IFN-gamma can also induce Ia-expression on astrocytes in vivo. Via local antigen presentation, IFN-gamma might thus play an important role in the development of MS lesions, while IFN-alpha might be involved in local immunosuppression.

Astrocytes↗
PubMed1988

Induction of oligodendrocyte proliferation and remyelination after chronic demyelination. Relevance to multiple sclerosis.

Optic nerve and spinal cord tissue from untreated guinea pigs with chronic relapsing experimental autoimmune encephalomyelitis, guinea pigs with experimental autoimmune encephalomyelitis in which the disease was treated with injections of myelin basic protein (MBP) combined with galactocerebroside (GC), and normal guinea pigs, has been studied morphologically, immunocytochemically and morphometrically. MBP/GC treatment induced widespread proliferation of oligodendrocytes and extensive central nervous system (CNS) remyelination in tissue from both sites. Whereas some oligodendrocytes within lesions from treated animals appeared to be derived from surviving cells which underwent mitosis, the frequent occurrence of nests of oligodendrocytes at the periphery of nerve fiber fascicles in optic nerve among perivascular astrocytic elements, raises the possibility that remyelinating oligodendrocytes might possess progenitors located in these regions. Observations from multiple sclerosis lesions showed that oligodendrocyte proliferation and CNS remyelination occur in human subcortical white matter, but to a lesser degree than that seen in the CNS of MBP/GC/treated guinea pigs. Immunocytochemical examination of CNS tissue from experimental autoimmune encephalomyelitis animals confirmed the morphologic identification of oligodendroglia. Preliminary morphometric analysis confirmed the impression of an increase in oligodendroglial cells in MBP/GC-treated animals. This increase was somewhat obscured statistically by a concomitant rise in the number of fibrous astrocytes. In view of the ability of oligodendrocytes to proliferate and produce new myelin in multiple sclerosis, the possibility is raised that an experimental immunologic approach similar to that employed here might have a beneficial effect in the human disease.

Animals↗
PubMed1987

Critical threshold for dose of myelin basic protein in murine autoimmune encephalomyelitis.

The clinical and pathologic features of experimental allergic encephalomyelitis (EAE) in the SJL mouse are described after inoculation with different amounts of myelin basic protein (MBP) in adjuvant. A dose threshold was apparent in that 400 micrograms produced the most severe central nervous system (CNS) changes. These comprised an extensive multifocal destructive myelitis with minimal demyelination. Doses greater than 400 microgram produced less white matter pathology and showed demyelinative rather than destructive lesions. No CNS parenchymal changes were seen in animals given less than 400 micrograms. Inflammation was invariably present in all animals showing CNS pathology, a prominent cellular component of which was the polymorphonuclear leukocyte. These findings illustrate the relationship of clinical signs and pathologic changes to the dose of MBP administered. Thus, it has been shown that the dose requirements for MBP-induced EAE in the SJL mouse are different from and greater than those for other species and that, unlike rats and guinea pigs, lesions were more extensive. Although demyelination was present, lesions tended to be destructive in type. This murine MBP model may serve as an experimental analog for the acute destructive myelopathies occasionally associated with the human autoimmune demyelinating disorders.

Animals↗
PubMed1987

Multiple sclerosis: relevance of class I and class II MHC-expressing cells to lesion development.

Expression of Class I (HLA-ABC) and Class II (HLA-Dr; Ia) major histocompatibility (MHC) antigens on endothelial cells and astrocytes was investigated in multiple sclerosis (MS) lesions of variable disease activity and in normal central nervous system (CNS) using immunocytochemical techniques. Findings were correlated to lesion pathology and to the presence and distribution of T cells, T cell subsets, and interleukin-2 (IL-2) receptor-bearing cells. HLA-ABC was present on virtually all endothelial cells in normal and pathologic tissue samples. Ia was absent from controls and was detectable on about 10% of CNS endothelial cells in MS. In normal CNS, astrocytes were Ia-negative and rarely expressed HLA-ABC. In MS, Class I and II MHC-positive astrocytes were found, and both displayed a high frequency in active lesions. Class I-reactive glia were primarily associated with T cell infiltrates and were less common in older lesions in which macrophages predominated. In contrast, Class II-positive astrocytes were found in all active MS lesions independent of the composition of inflammatory cells. Expression of HLA-ABC and Ia molecules on astrocytes in MS lesions could indicate their involvement in local presentation of antigen to cytotoxic (T8+) and helper/inducer (T4+) T cells, respectively. The observed distinct distribution patterns of HLA-ABC and Ia-positive astrocytes might suggest that cytotoxic T8+ cells are operative early during lesion development in MS. This could be followed by a more extensive Class II MHC-restricted helper T cell-mediated immune response which leads to selective destruction of myelin via activated macrophages.

Antibodies, Monoclonal↗
PubMed1986

Immunopathology of the lesion in chronic relapsing experimental autoimmune encephalomyelitis in the mouse.

To analyze immunopathologic events within the central nervous system (CNS) during various stages of actively induced chronic relapsing EAE in SJL/J mice, animals were sampled at various timepoints post inoculation (PI) and T cells, T-cell subsets, Ia+ cells and Ig+ cells, albumin, and Ig deposits were localized in frozen sections by immunocytochemical techniques. Furthermore, sections were stained for the demonstration of Ia antigen, myelin basic protein (MBP), and galactocerebroside (GC) on endothelial cells and astrocytes. During the acute phase of the disease, large numbers of all types of inflammatory cells studied (Lyt-1.2+, L3T4+, Lyt-2+, Ia+, Ig+) were randomly distributed throughout lesions, a finding similar to that described previously for acute EAE. A more distinct distribution pattern of infiltrating T cells was found during active chronic disease in that L3T4+ cells predominated within the CNS parenchyma, while Lyt-2+ cells were more numerous in meningeal and perivascular areas. During all chronic stages, a low-grade diffuse infiltration of the neuraxis by hematogenous cells was present. Ia and myelin antigens were detectable on some endothelial cells and astrocytes. Damage to the blood-brain barrier, as indicated by albumin and Ig deposits, was more extensive during the acute than during chronic stages of the disease. Taken in concert, the results further support the possibility of local antigen presentation on endothelial and astroglial cells and an essential involvement of helper (L3T4+) T cells in CNS lesion formation. These findings correlate well with events reported previously in acute and chronic multiple sclerosis lesions.

Animals↗
PubMed1985

Balo's concentric sclerosis: new observations on lesion development.

A 54-year-old woman with a four-month history of progressive neurological illness was found at postmortem examination to have lesions of Balo's concentric sclerosis. Balo lesions were found in several areas scattered widely throughout the central nervous system, including the spinal cord, a previously unreported location, and were studied by histological and ultrastructural methods. Balo lesions consisted of bands of intact myelin alternating with zones of demyelination. These lesions were centered on a perivascular cuff of inflammatory cells. The center of the lesion was the oldest area with the concentric rings of demyelination decreasing in age with increasing distance from the center. The bands of intact myelin comprised mainly remyelinated fibers, were similar to those seen at the edges of chronic active multiple sclerosis plaques, and may have represented the repaired margins of preceding episodes. The occurrence of small foci of acute demyelination centered on perivascular cuffs and other changes typical of both acute and chronic active multiple sclerosis may indicate that the lesion of Balo's concentric sclerosis represents an intermediate stage in the development of an established multiple sclerosis lesion.

Central Nervous System↗