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O Abramsky

Publications and source records attributed to O Abramsky.

At least 55 records · Page 3Linked to original sources
PubMed1997

Linomide activates the adrenocortical axis in the rat: inhibition of experimental autoimmune encephalomyelitis by linomide is not related to the increase of corticosterone.

Linomide is a synthetic compound that affects various immunological functions and inhibits experimental autoimmune encephalomyelitis (EAE). In the present study we evaluated the effect of linomide on the HPA axis functions under basal and stress-induced conditions and examined whether the effect of linomide on the HPA axis is involved in linomide-induced amelioration of EAE in rats. Linomide caused a significant increase of serum ACTH and corticosterone (CS). The adrenocortical response to various stress modalities as well as the negative feedback exerted by glucocorticoids was not affected. The marked reduction of thymus weight following linomide treatment was abrogated in adrenalectomized rats. The induction of EAE in adrenalectomized rats was completely inhibited by linomide treatment. These results suggest that the increased CS levels induced by linomide are responsible for the decrease in thymus weight but do not play a role in the therapeutic effect of this drug in EAE.

Adjuvants, Immunologic↗
PubMed1997

Reactivity of T cells from seronegative patients with myasthenia gravis to T cell epitopes of the human acetylcholine receptor.

Seronegative (SN) patients with myasthenia gravis (MG) have clinical and electrophysiologic features similar to those of seropositive (SP) patients, and they respond to the same therapeutic measures. However, because SN patients lack detectable (by standard radioimmunoassays) serum antibodies to acetylcholine receptor (AChR), which are considered to have a crucial role in MG, the pathophysiologic basis for the disease is not clear. We therefore compared the ability of peripheral blood lymphocytes (PBL) of SN patients (11) and SP patients (39) to respond to myasthenogenic T cell epitopes of human AChR. We tested two aspects that relate to T-cell immunity: 1) T cell responses to myasthenogenic peptides by proliferation and IL-2 production, and 2) the ability of antigen-presenting cells to bind these T-cell epitopes. T cells of SN patients did not differ from those of SP patients in their ability to respond and to bind the two human AChR-derived myasthenogenic peptides. This supports the belief that most SN patients indeed suffer from an autoimmune disease directed against the AChR. The presence of T-cell immunity in the absence of antibodies may emphasize the importance of AChR-specific T cells in MG.

Adult↗
PubMed1997

Detection of 14-3-3 protein in the CSF of genetic Creutzfeldt-Jakob disease.

The 14-3-3 protein, a protein involved in signal transduction, is present in the CSF of patients with Creutzfeldt-Jakob disease (CJD) and not in patients with other dementing diseases. We show here that this is also true for patients with E200K CJD, but not for healthy carriers of the mutation.

14-3-3 Proteins↗
PubMed1996

Peptide analogs to pathogenic epitopes of the human acetylcholine receptor alpha subunit as potential modulators of myasthenia gravis.

Myasthenia gravis is an autoimmune disease in which T cells specific to epitopes of the autoantigen, the human acetylcholine receptor, play a role. We identified two peptides, p195-212 and p259-271, from the alpha subunit of the receptor, which bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) from peripheral blood lymphocytes of myasthenia gravis patients and stimulated lymphocytes of >80% of the patients. We have prepared analogs of these myasthenogenic peptides and tested their ability to bind to MHC class II determinants and to interfere specifically with T-cell stimulation. We first determined relative binding efficiency of the myasthenogenic peptides and their analogs to APCs of patients. We found that single substituted analogs of p195-212 (Ala-207) and p259-271 (Lys-262) could bind to human MHC molecules on APCs as efficiently as the original peptides. Moreover, dual analogs containing the two single substituted analogs in one stretch (either sequentially, Ala-207/Lys-262, or reciprocally, Lys-262/Ala-207) could also bind to APCs of patients, including those that failed to bind one of the single substituted analogs. The single substituted analogs significantly inhibited T-cell stimulation induced by their respective myasthenogenic peptides in >95% of the patients. The dual analogs were capable of inhibiting stimulation induced by either of the peptides: They inhibited the response to p195-212 and p259-271 in >95% and >90% of the patients, respectively. Thus, the dual analogs are good candidates for inhibition of T-cell responses of myasthenia gravis patients and might have therapeutic potential.

Adult↗
PubMed1996

The clinical significance of a single abnormal immunoglobulin band in cerebrospinal fluid electrophoresis.

The finding of oligoclonal immunoglobulin (Ig) bands in the cerebrospinal fluid (CSF) is considered a cornerstone in the diagnosis of multiple sclerosis, but can be observed in other diseases as well. In a small subset of patients only a single Ig band, confined to the CSF, is identified. We evaluated the possible diagnostic significance of such a finding. Agarose gels of 6000 CSF samples were re-examined. In 1013 samples (16.8%) there were oligoclonal bands, and in 33 additional samples (0.55%) a single band was found (without a correlating band in the serum). Full data was available for 20 single band patients. Seven patients had clinical definite multiple sclerosis. Of these, 6 had a typically prominent affective disorder and 5 had a relatively malignant course of disease. Seven additional patients had other white matter diseases of the central nervous system (CNS). The remaining patients had inflammatory diseases of peripheral nerves or CNS gray matter and non-inflammatory brain diseases. The frequency of demyelinating diseases of the CNS in patients with a single abnormal Ig band in the CSF was significantly less than in a control group of patients with oligoclonal bands. In conclusion, the finding of a single Ig band confined to the CSF may hint for a disease other than multiple sclerosis, and mark an aggressive course with affective disorder in those who do have multiple sclerosis.

Demyelinating Diseases↗
PubMed1996

Serum Cu/Zn superoxide dismutase activity is reduced in sporadic amyotrophic lateral sclerosis patients.

Accumulated evidence implies that mutations in the gene coding for Cu/Zn superoxide dismutase (SOD) are associated with the pathogenesis of the familial form of amyotrophic lateral sclerosis (ALS). The clinical and pathological similarities of the familial and the sporadic forms of the disease may suggest that abnormal SOD activity takes also part in the pathogenesis of sporadic ALS. We therefore measured serum SOD activity in fifteen sporadic ALS patients. Mean serum SOD activity was 1.15 +/- 0.40 u/ml in ALS patients, 1.50 +/- 0.45 u/ml. in patients with other neurological disorders and 1.45 +/- 0.45 u/ml in.healthy controls (p < 0.021 and p < 0.031 respectively). If this sporadic ALS-related reduction in serum SOD activity will be confirmed in the diseased nervous system tissue, it may suggest that abnormal SOD activity is also associated with the motor neuron damage in the sporadic form of ALS.

Adult↗
PubMed1996

Immunomodulation with linomide: possible novel therapy for multiple sclerosis.

Linomide, a synthetic quinoline carboxamide, has the ability to stimulate various lymphocyte subpopulations. We have shown its inhibitory effect on the clinical and histological signs of acute and chronic relapsing EAE. In these models linomide induces suppression of lymphocyte response to antigens, production of autoantibody, antigen presentation to specific T-cell lines and Mac-I expression, and induces activation of NK and suppressor-inducer cells. We have subsequently shown its inhibitory effect on clinical and MRI signs of patients with secondary progressive multiple sclerosis. Results of a double blind, placebo controlled, short term pilot study with p.o. linomide, showed a significant effect on the clinical disability scale (EDSS) (P = 0.045) and on the mean total number of new lesions in serial monthly MRI scans (P = 0.021). The increase of CD45Ra, CD8 and CD16 positive cells in linomide treated patients may indicate the importance of suppressor-inducer, suppressor and NK cells for the inhibition of the autoimmune response in the disease.

Adjuvants, Immunologic↗
PubMed1996

Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation.

Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that increases the natural killer cell activity. We previously demonstrated that linomide effectively inhibited the clinical and histopathologic signs of acute and chronic relapsing experimental autoimmune encephalomyelitis. We report a double-blind, placebo-controlled study to evaluate tolerability and to obtain preliminary indications of the clinical efficacy of linomide on secondary progressive MS. Thirty patients suffering from clinically definite and laboratory-supported secondary progressive MS, with an expanded disability status scale (EDSS) of 3.0 to 7.0, were included in this study. Patients were treated daily with linomide (2.5 mg) or placebo orally and were followed up for side effects and changes in their neurologic status; monthly MRI scans were taken throughout the treatment period. Twenty-four patients completed at least 6 months of treatment. Mild to moderate side effects, including muscle pains, arthralgia, and edema, were present in 11 of the 15 patients receiving placebo and in 13 of the 15 patients treated with linomide. At 24 weeks, the mean shift in EDSS was +0.272 +/- 0.156 in the placebo group versus -0.166 +/- 0.167 in the linomide group (p = 0.0451). The percentage of patients with evidence of "activity" on their MRI (new, enlarging, or new gadolinium diethylenetriaminepentaacetic acid [Gd-DTPA]-enhancing lesions) throughout the treatment period was 75% in the placebo group and 33% in the linomide group (p = 0.0205). The mean total number of new Gd-DTPA-enhancing lesions per MRI scan for the same period was 0.42 +/- 0.143 in the placebo group and 0.19 +/- 0.114 in the linomide group (p = 0.0387). In this study, linomide proved to be safe and well tolerated in patients with secondary progressive MS. In addition, our results indicate that linomide tends to inhibit the progression of the disease, especially preventing the appearance of new active lesions in the MRI scans. Based on these results, two multicenter phase III trials are currently under way in the United States and in Europe and Australia.

Adjuvants, Immunologic↗
PubMed1996

Control of stroma-dependent hematopoiesis by basic fibroblast growth factor: stromal phenotypic plasticity and modified myelopoietic functions.

It has been suggested that basic fibroblast growth factor (bFGF) affects hematopoietic cells directly and that it may also act indirectly by modulating stromal cell functions. We tested the response of phenotypically and functionally distinct stromal cell clones to this cytokine. We studied cell phenotype, the composition and organization of cytoskeleton and extracellular matrix, the ability to repopulate 'wounded areas', the expression of cytokine genes, and the capacity of the stroma to support long-term hematopoiesis in vitro. Although the impact of bFGF on cell growth was small, it induced a prominent morphological change in three stromal cell types that we tested. We analyzed the molecular basis for this change: bFGF modified the protein expression of alpha-smooth muscle actin (alpha-SMA), tropomyosin, alpha-tubulin, fibronectin and paxillin in a distinct manner characteristic of each of the stromal cell types. Immunofluorescence analysis of these proteins revealed profound changes in the cytoskeleton and extracellular matrix (ECM) networks accompanied by increased ability of the 14F1.1 stromal cells to scatter in in vitro 'wounded' areas. Furthermore, although only limited changes were monitored in the expression of cytokine genes, the ability of the stromal cells to support hematopoiesis was markedly modified. Thus bFGF profoundly changes the cellular organization of stromal cells, their adhesion and their motility properties. These changes are associated with modified capacity to support hematopoiesis in culture.

Adipocytes↗
PubMed1995

Cytokeratin expression in human thymus: immunohistochemical mapping.

Cytokeratin expression in normal postnatal human thymus was studied immunohistochemically by using monoclonal antibodies against various cytokeratin polypeptides. An attempt was made to characterize cell populations giving rise to the cornified structures of Hassal's corpuscles. Monoclonal antibody KB-37, a marker of squamous epithelium basal cells, was applied to distinguish the earliest cells capable of undergoing squamous differentiation. Parts of the subcapsular epithelium were extensively stained with this reagent. This epithelium, like the basal layer of certain squamous epithelia, exhibited a high incidence of cytokeratins 13 and 14, and pronounced expression of cytokeratin 19. Simple epithelium cytokeratins 8, 18, and 19 were present in the cortex. Scattered cells reacted with KB-37 antibody. All stellate epithelial cells in the medulla were positive for cytokeratin 19. Most of the medullar epithelial cells were positive for cytokeratins 13, 14 and 17 of complex epithelium, in contrast to the cortex, where only a few cells were positive for these cytokeratins. A significant proportion of the medullar cells was positive for KB-37 antigen. Cytokeratins 8 and 18 were expressed in single cells and in groups of cells surrounding Hassal's corpuscles. The outermost cells of these corpuscles were positive for cytokeratin 19 and KB-37. In the peripheral parts of Hassal's corpuscles, simple epithelium cytokeratins 7, 8, 18, and cytokeratins 4, 13, 14, and 17, characteristic of stratified nonkeratinizing epithelia, were coexpressed with keratinization-specific cytokeratins 10/11. The inner parts of the swirls were uniformly positive for cytokeratins 10/11. However, the expression of other cytokeratins was reduced.

Antibodies, Monoclonal↗
PubMed1995

Binding of peptides of the human acetylcholine receptor alpha-subunit to HLA class II of patients with myasthenia gravis.

MG is an autoimmune disease in which T cells specific to T-cell epitopes of the human acetylcholine receptor play a role. We have identified two peptides, p195-212 and p259-271, of the human acetylcholine receptor alpha-subunit, to which PBLs of MG patients responded by proliferation. Nevertheless, proliferation assays are relatively complicated to perform and might be affected by medications taken by the patients. Therefore, we tested the possibility of using a different assay to determine recognition of these peptides by MG patients. Thus, we performed a direct binding assay using biotinylated peptides and APCs from peripheral blood of MG patients and healthy controls. With this assay we detected the binding of the two peptides to the surface of intact APCs of both MG patients and control donors. Moreover, the presentation of peptide p259-271 by individuals with MG was significantly higher than that observed in healthy subjects. The peptides were specifically bound to HLA class II determinants on the APCs, as shown by inhibition with antibodies to the HLA class II haplotypes of the individuals investigated. Moreover, the binding of these peptides was in correlation with their ability to induce specific proliferative responses of peripheral blood T cells of these patients. The ability to screen for potentially pathogenic epitopes in each patient is of importance for the future design of specific inhibitory analogues that might be used to treat MG.

Amino Acid Sequence↗
PubMed1995

Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT).

MRL-lpr/lpr mice spontaneously develop a severe autoimmune syndrome, characterized by massive generalized lymphadenopathy, arthritis, arteritis, dermatitis and immune complex-mediated glomerulonephritis. Bone marrow transplantation (BMT) from MHC-matched systemic lupus erythematosus (SLE)-resistant donors to susceptible recipients has proved effective in correcting autoimmune manifestations in autoimmune-prone mice. We investigated the effect of syngeneic BMT from MRL/lpr (donor) to immunocompromised MRL/lpr (recipient), after purging the bone marrow inoculum with MoAbs against mature T cells (anti-Thy 1.2). All the untreated mice developed lymphadenopathy and by the age of 36 weeks five of the eight were dead; in contrast, all the mice which underwent syngeneic BMT following acute immunosuppression with total body irradiation (900 cGy) (TBI) remained disease-free. In an additional experiment, it was found that conditioning with cyclophosphamide (CY) before BMT was more effective than TBI in inhibiting delayed-onset autoimmune manifestations (mean survival 350 days in the CY group and 305 days in the TBI group, versus 197 days in untreated controls). Under both immunosuppressive regimens T cell-depleted bone marrow grafts produced far better results than did unmanipulated BMT. Following syngeneic BMT the incidence of proteinuria and the level of serum anti-DNA (dd) antibodies were significantly reduced, compared with that of the age-matched untreated controls. CY was more effective than TBI in reducing the anti-DNA titres. Likewise, T depletion of bone marrow inocula before BMT induced a more drastic drop in autoantibodies, following both CY and TBI conditioning protocols. After syngeneic BMT (either CY or TBI) no signs of lymphadenopathy were observed even at an advanced age. Upon histopathological examination, the BMT-treated mice displayed normal glomeruli with occasional minimal signs of glomerulonephritis. Syngeneic T cell-depleted BMT following acute cytoreduction of anti-self immune lymphocytes may represent a new therapeutic approach for drug-resistant autoimmune diseases.

Animals↗
PubMed1995

Hereditary leukoencephalopathy and palmoplantar keratoderma: a new disorder with increased skin collagen content.

We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of early-childhood-onset palmoplantar keratoderma followed in adulthood by progressive tetrapyramidal syndrome and cognitive impairment. Of the four affected siblings, two were available for evaluation. Investigation disclosed cerebral white-matter involvement on MRI and arylsulfatase A pseudodeficiency carrier state, which was also identified in clinically unaffected family members. Since skin biopsies showed dermal connective tissue abnormalities, we studied collagens I, III, and VI biosynthesis. Northern blotting of RNA extracted from cultured skin fibroblasts revealed an increased steady-state messenger RNA (mRNA) level of alpha 1(VI) collagen, whereas no differences were detected for pro alpha 1(I), pro alpha 1(III), and tropoelastin mRNAs. The skin content of collagen and total protein was higher in the patients than in controls. We suggest that an extracellular matrix abnormality may be involved in the pathogenesis of this disorder.

Adult↗