Search PubMed⌕ Search

Biomedical subjects

R Gold

Publications and source records attributed to R Gold.

At least 145 records · Page 8Linked to original sources
PubMed1995

T cell antigenic and neuritogenic activity of recombinant human peripheral myelin P2 protein.

The major neuritogenic protein of peripheral nerve myelin is the P2 protein. Human P2 is a candidate autoantigen in inflammatory demyelinating diseases of the peripheral nervous system. Since human P2 is not readily available, we produced full-length recombinant human P2 protein (rhP2) in Escherichia coli. RhP2 was recognized by neuritogenic rat T cell lines and induced experimental autoimmune neuritis in Lewis rats. Production of rhP2 allowed the generation of human T cell lines reactive to the autologous protein. Studies of human T cell autoreactivity as well as efforts to use hP2 as a tolerogen will be facilitated by the large-scale expression of rhP2.

Amino Acid Sequence↗
PubMed1995

Synergistic effect of IFN-gamma and TNF-alpha on expression of immune molecules and antigen presentation by Schwann cells.

Neonatal rat Schwann cells were characterized with regard to their immune functions in vitro. Without stimulation they displayed low levels of ICAM-1, but not of MHC class II gene products on their surface. Expression of both immune molecules was upregulated by IFN-gamma. TNF-alpha acted synergistically, but had no effect when given alone. ICAM-1 expression reached its maximum within 24 hr, whereas I-A plateaued only after 3 days of cytokine treatment. Increased expression of recognition molecules on Schwann cells correlated well with enhanced activation of CD4+ autoimmune T cell lines between Day 1 and 2. T cell activation was blocked by adding monoclonal antibodies directed against I-A molecules, whereas ICAM-1-specific antibodies exerted a mild costimulatory effect. We conclude that Schwann cells may exert potent immunoregulatory functions by expressing MHC and adhesion molecules, which may be further upregulated by Th1-type cytokines released by immunoinflammatory T cells in the lesion.

Animals↗
PubMed1995

T-cell receptor (TCR) usage in Lewis rat experimental autoimmune encephalomyelitis: TCR beta-chain-variable-region V beta 8.2-positive T cells are not essential for induction and course of disease.

Predominant usage of V beta 8.2 gene segments, encoding a T-cell receptor (TCR) beta chain variable region, has been reported for pathogenic Lewis rat T cells reactive to myelin basic protein (MBP). However, up to 75% of the alpha/beta T cells in a panel of MBP-specific T-cell lines did not display TCR V beta 8.2, V beta 8.5, V beta 10, or V beta 16 elements. To further investigate TCR usage, we sorted the T-cell lines for V beta 8.2- and V beta 10-positive T cells or depleted the lines of cells with these TCRs. V beta 8.2-positive T cells and one of the depleted T-cell lines strongly reacted against the MBP peptide MBP-(68-88). The depleted T-cell line caused marked experimental autoimmune encephalomyelitis (EAE) even in Lewis rats in which endogenous V beta 8.2-positive T cells had been eliminated by neonatal treatment with anti-V beta 8.2 monoclonal antibodies. T-cell hybridomas generated from this line predominantly used V beta 3 TCR genes coexpressed with TCR V alpha 2 transcripts, which were also used by V beta 8.2-positive T cells. Furthermore, V beta 10-positive T cells reactive to MBP-(44-67) were encephalitogenic when injected immediately after positive selection. After induction of EAE by sorted V beta 8.2- or V beta 10-positive T-cell lines, immunocytochemical analysis of the spinal cord tissue showed a predominance of the injected TCR or of nontypable alpha/beta T cells after injection of the depleted line. Our results demonstrate heterogeneity of TCR beta-chain usage even for a single autoantigen in an inbred strain. Moreover, V beta 8.2-positive T cells are not essential for the induction and progression of adoptive-transfer EAE.

Amino Acid Sequence↗
PubMed1995

Mitochondrial dysfunction in adult-onset myopathies with structural abnormalities.

Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.

Adult↗
PubMed1995

Mafosfamide induces DNA fragmentation and apoptosis in human T-lymphocytes. A possible mechanism of its immunosuppressive action.

Cyclophosphamide, an alkylating agent belonging to the family of nitrogen mustards, is commonly used to treat progressive autoimmune diseases in humans. At the molecular level, its cytotoxicity results from DNA double strand crosslinks and, at higher concentrations, from DNA strand breaks. At the cellular level, cyclophosphamide may selectively affect mature lymphocytes with relative sparing of the respective precursor cells. In this study, we show that 4-hydroxycyclophosphamide (4-OH-CP), the active metabolite of cyclophosphamide, induces apoptosis in mature human lymphocytes at concentrations that are achieved in vivo. Since cyclophosphamide requires enzymatic conversion in the liver to yield its active metabolite, 4-OH-CP was generated in vitro by non-enzymatic hydrolysis of mafosfamide. Apoptotic cell death of lymphocytes was characterized by typical morphological changes, nucleosomal DNA fragmentation, and quantified by 3'-OH end labeling of fragmented DNA. The percentage of apoptotic cells both depended on drug concentration and time of exposure. Cycloheximide or ZnSO4 did not suppress 4-OH-CP induced apoptosis. Etoposide, a topoisomerase II inhibitor known to induce apoptosis in human tumor cell lines like 4-OH-CP, did induce detectable DNA fragmentation in only a minor proportion of T-lymphocytes but suppressed T-cell proliferation.

Adult↗
PubMed1995

Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis.

The nitric oxide (NO) synthase pathway is activated during experimental autoimmune inflammation of the central nervous system, and administration of aminoguanidine, an inhibitor of the cytokine-inducible NO synthase (NOS), ameliorated the disease course of autoimmune encephalomyelitis in the SJL mouse. We studied the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune neuritis (EAN) and experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. NG-L-monomethyl-arginine (L-NMMA), a competitive inhibitor of NOS, partially suppressed T cell line-mediated EAN, but not myelin-induced EAN, myelin basic protein (MBP)-induced EAE, or T cell line-mediated EAE. Aminoguanidine (AG), a selective inhibitor of the cytokine-inducible NOS, enhanced MBP-induced EAE, but had no significant effects on myelin-induced EAN. Two other NOS inhibitors, nitro-arginine methyl-ester and N-nitro arginine, had only little or no effects in EAN and EAE. The administration of NOS inhibitors showed some striking effects in EAN and EAE, but the observed diversity of actions points to a much more complex role of the NO pathway than previously suggested.

Acetates↗
PubMed1995

Gene transfer through the blood-nerve barrier: NGF-engineered neuritogenic T lymphocytes attenuate experimental autoimmune neuritis.

Nerve-specific autoimmune T lymphocytes were used as vehicles to deliver therapeutically useful neurotrophic factors across the endothelial blood-nerve barrier. P2 protein-reactive T-lymphocyte lines from Lewis rats were transduced with a recombinant retrovirus containing the mouse nerve growth factor (NGF) gene. The engineered T cells released high amounts of NGF dependent on antigenic stimulation in vitro. After intravenous injection, the T cells infiltrated the rat peripheral nervous system and persisted there for at least two weeks. Local release of NGF from engineered T cells was demonstrable by immunocytochemistry and by an anti-inflammatory effect on infiltrating macrophages.

Animals↗
PubMed1995

[Therapy with immunoglobulins in neurologic autoimmune diseases. Indications and mechanism of action].

Intravenous 7S-immunoglobulins (IVIg) are made of intact human IgG from pooled plasma by using cold alcohol fractionation followed by further purification steps to remove complement-activating material. The half-life of IVIg in vivo is approximately 3 weeks. Favourable effects were reported in patients with myositis and multifocal motor neuropathy who did not respond to established immunosuppressive therapies, and in Guillain-Barre-Syndrome and chronic inflammatory demyelinating polyneuropathy. No definite recommendation can presently be made concerning their use in other neuromuscular disorders and in multiple sclerosis where the results of ongoing and future controlled studies have to be awaited. Some of the possible mechanisms of immunoglobulin efficacy have been delineated in animal models and tissue culture: anti-idiotypic suppression, down-regulation of B- and T-cell activation, blockade of Fc receptors on phagocytic cells, neutralisation of superantigen and complement mediated effects, down-regulation of cytokine production and neutralisation of cytokines. Few side effects have been reported to date. However, treatment is expensive when compared with established immunosuppressive therapies. The main risk consists of the transmission of infectious agents that can only be excluded if the manufacturing process is optimal. A broad and uncontrolled use of immunoglobulins in the treatment of neurologic disorders is discouraged.

Autoimmune Diseases↗
PubMed1995

Why we need to rethink AIDS education for gay men.

This paper examines critically the issue of prevention of HIV infection for gay men. Evidence for the persistence of unsafe sexual behaviour in gay men is provided, followed by discussion of obstacles to the development of effective interventions to initiate and maintain safer sex behaviour.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Non-neural-specific T lymphocytes can orchestrate inflammatory peripheral neuropathy.

Neural-specific T lymphocytes are held to play a pathological role in inflammatory peripheral nerve disorders such as the Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Here, non-neural-specific T-cell-mediated inflammation was studied in peripheral nerves in Lewis rats by systemic transfer of ovalbumin-specific activated T cells followed by intraneural injection of ovalbumin. Rapid endoneurial perivenular infiltration of alpha beta T cells and ED1+ macrophages occurred with ovalbumin injection following transfer of 2 x 10(6) T cells. This cellular infiltration and accumulation produced marked increases in blood-nerve barrier (BNB) permeability. In contrast, control casein injections produced neither significant cell accumulation nor BNB permeability changes. Transfer of a higher number of T cells (5 x 10(6)) induced severe Wallerian degeneration and nerve conduction failure in ovalbumin injected nerves. Fewer T cells (5 x 10(5)) induced conduction block and mild demyelination which were markedly augmented by systemic cotransfer of anti-myelin immunoglobulin. This study demonstrates that activated T cells of non-neural specificity can accumulate in peripheral nerve, produce dramatic changes in BNB permeability and with intravenous anti-myelin antibody orchestrate primary demyelination or axonal degeneration in a dose-dependent fashion.

Animals↗
PubMed1995

Intravenous glucocorticosteroid treatment augments apoptosis of inflammatory T cells in experimental autoimmune neuritis (EAN) of the Lewis rat.

Apoptosis plays a critical role in natural recovery from experimental autoimmune disorders of the nervous system. Here we investigated in experimental autoimmune neuritis (EAN) whether apoptosis is augmented by high-dose corticosteroids, the mainstay of therapeutically active compounds in this group of disorders. Adoptive transfer EAN was induced by intravenous injection of P2-specific T cell blasts. At disease onset or at the maximum of disease two pulses of steroids were given within 12 hours, and animals were sacrificed 6 hours later. Steroid therapy significantly reduced T cell infiltration in sciatic nerve. Treatment on both day 4 and day 7 caused a significant increase of T cell apoptosis (42% vs 8.4% in placebo-treated animals on day 4, p < 0.05; 22.5% vs 7.0% on day 7, p < 0.05) in sciatic nerve as assessed by molecular labeling techniques. In addition, reduction of body weight and thymus weight and augmentation of thymocyte apoptosis were observed in steroid recipients. Steroid treatment markedly reduced cellular proliferation in lymphoid organs as measured by bromodeoxyuridine incorporation. Glucocorticosteroid treatment augments T cell apoptosis in inflammatory lesions of the peripheral nervous system, and this may add to their anti-inflammatory properties mediated by downregulation of cytokine expression.

Animals↗
PubMed1995

Circulating adhesion molecules and inflammatory mediators in demyelination: a review.

Accumulating evidence shows that adhesion molecules are critically involved in inflammatory demyelination in the focusing of systemic immune responses into the target tissue, the nervous system. Adhesion molecules are upregulated through the action of cytokines. Tumor necrosis factor alpha appears to be of prime importance. Circulating adhesion molecules probably reflect acute inflammatory episodes in the central and peripheral nervous system, but may also function to modulate ongoing inflammatory responses. Cytokines released by TH1 cells render resident and immigrant macrophages, as well as microglia, activated to synthesize and release increased amounts of inflammatory mediators, such as oxygen radicals, nitric oxide metabolites, and components of the complement system. A more detailed understanding of the sequence of immunopathologic events that culminate in myelin damage in the central and peripheral nervous systems has revealed several sites to which more specific and effective immunointervention can be targeted.

Cell Adhesion Molecules↗
PubMed1995

Is there a rationale for iron supplementation in the treatment of akathisia? A review of the evidence.

BACKGROUND: An association found between akathisia and iron deficiency led to the suggestion that iron supplementation might be a useful therapeutic intervention for patients with akathisia. There is, however, a body of literature on the abnormal deposition of iron in the brain in several degenerative diseases like Hallervorden-Spatz syndrome, Parkinson's disease, and Alzheimer's disease. Given the ability of neuroleptics to chelate iron and promote its deposition in the brain, we questioned whether peripheral measures of iron are an accurate reflection of central iron levels and thus whether there was a rationale for iron supplementation in akathisia. METHOD: A MEDLINE search for literature relating to iron and akathisia, tardive dyskinesia, and Parkinson's disease was carried out and critically reviewed. RESULTS: Evidence is presented for the ability of neuroleptics to chelate iron, mobilize it from peripheral stores, and deposit it in the basal ganglia. The effect of iron on dopaminergic receptor activity in brain and the potential role of iron in degenerative and neuroleptic-induced movement disorders are reviewed. The preponderance of the evidence shows a relationship between iron excess in the basal ganglia and the movement disorders. We found no studies that have examined the regulation of central levels of iron in patients with akathisia. CONCLUSION: The rationale for iron supplementation in the treatment of akathisia is relatively weak, and there are potentially adverse long-term consequences as outlined in our review. More research is required to directly measure the level of iron in the brain of patients with akathisia, e.g., using magnetic resonance imaging, before such therapeutic intervention can be recommended.

Akathisia, Drug-Induced↗
PubMed1994

Apoptotic cell death of T-lymphocytes in experimental autoimmune neuritis of the Lewis rat.

The present study describes apoptosis of T-lymphocytes in the sciatic nerve in experimental autoimmune neuritis (EAN), a T-cell mediated disorder of the peripheral nervous system (PNS). Morphological signs characteristic for apoptotic cell death were found from day 4 onwards, peaking at day 7. Apoptosis of T-cells could be detected throughout the subsequent recovery period. In situ nick translation (ISNT) followed by immunocytochemical analysis confirmed the presence of DNA fragmentation in T-lymphocytes. We thus show for the first time that apoptosis is not a unique elimination mechanism of inflammatory T-cells in the central nervous system (CNS), but is operative in the PNS as well although at a lesser degree. Identifying the underlying mechanisms may provide a basis for the development of new therapeutic strategies in autoimmune disorders.

Animals↗
PubMed1994

A 400-kb tandem duplication within the dystrophin gene leads to severe Becker muscular dystrophy.

We describe a family with a large duplication of exons 2-16 of the dystrophin gene. It was characterized by immunocytochemistry, field-inversion gel electrophoresis and quantitative Southern blots. Our observations are of clinical interest in that they demonstrate an intermediate disease course despite a disrupted reading frame of dystrophin as postulated from exon-intron boundaries. We discuss possible mechanisms which may explain the unusual phenotype in our patient.

Adult↗