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E Mozes

Publications and source records attributed to E Mozes.

At least 73 records · Page 4Linked to original sources
PubMed1995

Beneficial effects of bone marrow transplantation on the serological manifestations and kidney pathology of experimental systemic lupus erythematosus.

We have recently shown, using allogeneic bone marrow transplantation (BMT), that susceptibility of mice to the induction of experimental systemic lupus erythematosus (SLE) is determined by bone marrow (BM)-derived cells. In the present study we investigated the ability of BMT to cure mice already afflicted with this disease. We found that transplantation of SLE-diseased mice, with T-cell-depleted BM cells either from an SLE-resistant or from an SLE-susceptible donor, caused a significant reduction in the levels of anti-16/6 Id, 16/6 Id+, anti-ssDNA, and anti-dsDNA autoantibodies, compared to untreated SLE-afflicted mice. Interestingly, the reduction caused by the BMT of SLE-susceptible donor cells in the levels of the two former antibodies was significantly milder than the reduction caused by BMT of SLE-resistant cells. In contrast, the reduction in the levels of anti-ssDNA and anti-dsDNA antibodies, following BMT of cells from SLE-susceptible donors, did not differ from that caused by transplantation of BM cells from SLE-resistant donors. Following the transplantation of SLE-resistant but not of SLE-susceptible BM cells, a significant reduction was observed in the frequency of mice suffering from SLE-related immune complex deposits in their kidneys. If performed at advanced stages of the disease, transplantation of SLE-resistant BM cells into experimental SLE-diseased mice still led to a reduction in the levels of SLE-related autoantibodies, although to a lesser extent, but failed in improving kidney pathology. In conclusion, our data demonstrate that bone marrow transplantation has a beneficial effect on mice afflicted with experimental SLE.

Animals↗
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

The pathogenic human monoclonal anti-DNA that induces experimental systemic lupus erythematosus in mice is encoded by a VH4 gene segment.

Systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human anti-DNA IgM mAb that was derived from a patient with cold agglutinin disease. The latter anti-DNA mAb expresses the common idiotype (Id) designated 16/6 Id. The original human hybridoma 16/6 that secreted an IgM antibody that bound ssDNA and carried the 16/6 Id had switched in culture to secrete an IgG molecule. Herein we show that the IgG 16/6 antibody contains the previously reported characteristics of the original IgM 16/6 mAb: it expresses the 16/6 Id and is capable of inducing experimental SLE in susceptible mouse strains. The identify of the IgG 16/6 anti-DNA mAb to the original IgM mAb was shown both by serological techniques and at the T cell level. The human IgG 16/6 mAb was found to be encoded by a germline gene from the human VH4 gene family, with high similarity to the germline gene VH4.21 that was previously shown to code for anti-DNA antibodies isolated from SLE patients. The VH4.21 germline gene was found to also code for most antibodies with cold agglutinin activity that were isolated from patients with cold agglutinin disease.

Amino Acid Sequence↗
PubMed1995

Methotrexate treatment in murine experimental systemic lupus erythematosus (SLE); clinical benefits associated with cytokine manipulation.

The objective of this study was to determine the effects of Methotrexate (MTX) on the development and the course of experimental murine SLE, as well as on the cytokine profile involved in the disease. SLE was induced in naive BALB/c female mice by injection of the human anti-DNA MoAb bearing a common idiotype (16/6 Id). Six weeks following immunization, when high levels of autoantibodies were demonstrated, the mice were treated with MTX (2 mg/kg once a week) for a period of 10 months. MTX treatment had no effect on 16/6 Id-induced autoantibody production. However, MTX treatment had beneficial effects on the clinical manifestations of the experimental disease (i.e. leucocyte counts, levels of protein in the urine and immune complex deposits in the kidneys). Thus, only 20% of 16/6 Id-immunized BALB/c mice that were treated with MTX had immune complex deposits in their kidneys compared with 100% of SLE-afflicted BALB/c mice that were not treated. We have observed a significant elevation in IL-1, tumour necrosis factor (TNF) and IL-10 secretion in BALB/c mice afflicted with experimental SLE. IL-2, IL-4, IL-6 and interferon-gamma (INF-gamma) levels were decreased in these mice compared with the levels detected in healthy controls. Treatment with MTX reversed the levels of all the above cytokines to normal levels observed in control mice. These studies demonstrate therapeutic effects of MTX on murine experimental SLE. The normal cytokine profile observed following treatment with MTX is suggested to play a role in the amelioration of the clinical manifestations of experimental SLE.

Animals↗
PubMed1995

Autoantibodies to prostate specific antigen in patients with benign prostatic hyperplasia.

PURPOSE: We tested for a possible autoimmune process in benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Titers of IgG antibodies to prostate specific antigen (PSA) were measured in the sera of 85 BPH patients, 20 controls and 17 chronic prostatitis patients by enzyme-linked immunosorbent assay. RESULTS: The mean anti-PSA titers in the BPH group were significantly higher than in the controls and prostatitis group (p < 0.0005). Accordingly, 59% of BPH patients could be defined as responders to PSA compared to none among the controls (p < 0.0005). CONCLUSIONS: Circulating autoantibodies to PSA were shown to exist in the sera of BPH patients. This observation suggests that autoimmune processes may have a role in BPH.

Adult↗
PubMed1994

Methimazole prevents induction of experimental systemic lupus erythematosus in mice.

Experimental SLE can be induced in mice by immunization with a human mAb to DNA (16/6Id). Immunized mice develop Abs to the 16/6Id immunogen, DNA, and nuclear Ags. Subsequently, clinical manifestations of disease develop, including leukopenia, proteinuria, and immune complex deposits in the kidney. MHC class I Ags play a critical role in the induction of experimental SLE, as demonstrated by the finding that class I-deficient mice are resistant to disease induction. This finding suggested that agents that reduce MHC class I expression might mitigate experimental SLE in normal mice. These studies report that methimazole, which has been shown to repress class I transcription in some cell lines, reduces class I expression on PBLs in vivo and prevents the development of clinical manifestations of SLE in 16/6Id-immunized mice. These data suggest that methimazole, which has been used in the treatment of Graves' disease, may be useful in the clinical treatment of SLE and other autoimmune diseases.

Animals↗
PubMed1994

Dichotomy between the T and the B cell epitopes of the synthetic polypeptide (T,G)-A--L.

Studies with the well-characterized, synthetic, random-multichain polypeptide poly(LTyr,LGlu)-poly(DLAla)-poly(LLys) (T,G)-A-L) led to the discovery of determinant-specific genetic control of the immune response, as well as to other immunological phenomena. Moreover, the tetrapeptide TyrTyrGluGlu built on the same backbone ("(T-T-G-G)-A--L") was found to represent its major B cell epitope. We have recently shown that for interaction with major histocompatibility complex class II molecules and stimulation of T cells, (T,G)-A--L requires proteolytic processing and the resulting T cell epitopes are close to the N termini of the branched polymer's side chains. Thus, we were interested to elucidate the major T cell epitope of (T,G)-A--L, by using the ordered polypeptides (T-T-G-G)-A--L and (T-G-T-G)-A--L, in which only the two internal amino acids of the tetrapeptide attached to the side chains are switched. We established T cell lines to these antigens, and found that the ordered analog (T-T-G-G-)-A--L, which was defined as the B cell epitope of (T,G)-A--L, did not represent its T cell epitope, whereas (T-G-T-G)-A--L, to which only a minor anti-(T,G)-A--L Ab response was directed, was found to be its major T cell epitope. In addition, there was no cross-reaction between (T-G-T-G)-A--L and (T-T-G-G)-A--L at the T cell level, similar to the lack of cross-reaction of their antibodies. Analysis of the repertoire of the T cell receptors used by these lines revealed that the (T,G)-A--L and the (T-T-G-G)-A--L specific T cell lines were not restricted in their V alpha and V beta TCR usage, whereas the (T-G-T-G)-A--L-specific line was restricted by both V alpha and V beta T cell receptor gene products. This difference might be due to the thymus-independent characteristics previously described for the latter antigen.

Animals↗
PubMed1994

Fine specificity of T cell lines and clones that are capable of inducing autoimmune manifestations in mice.

Myasthenia gravis is a T-cell-regulated, antibody-mediated autoimmune disease. The synthetic peptides p195-212 and p259-271, which represent sequences of the human acetylcholine receptor alpha-subunit, preferentially stimulated T cells of patients with myasthenia gravis and were found to be immunodominant T cell epitopes in SJL and BALB/c mice, respectively. Therefore, we established a p195-212-specific T cell line from SJL mice and a p259-271-specific T cell line from BALB/c mice. N- and C-terminal truncated and/or extended peptides differed in their ability to stimulate proliferative responses of the lines and of their derived clones. Activated cells of the lines were inoculated into naive syngeneic mice. In both strains of mice, peptide-specific antibodies and antibodies to the murine acetylcholine receptor were detected. In addition, decremental compound muscle action potentials consistent with impairment of neuromuscular transmission were recorded from the line-inoculated mice. Thus, these T cell lines, clones, and epitopes constitute a useful model for investigating T cell pathogenicity in autoimmune manifestations related to myasthenia gravis.

Action Potentials↗
PubMed1994

Neonatal lupus erythematosus with cardiac involvement in offspring of mothers with experimental systemic lupus erythematosus.

Neonatal lupus erythematosus (NLE) syndrome is characterized by a transient dermatitis, a variety of systemic and hematological abnormalities, and isolated cases of congenital complete heart block. The latter has been reported to be due to the presence of autoantibodies specific to La (SS-B) and/or Ro (SS-A). As female mice with experimental systemic lupus erythematosus (SLE) induced by immunization with the human monoclonal anti-DNA antibody bearing the 16/6 Id produce variety of autoantibodies including anti-Ro and anti-La antibodies, we looked for NLE related symptoms in the murine model. Offspring of BALB/c mice with SLE possessed high levels of autoantibodies that declined gradually till reduced to normal levels at day 60 after delivery. Electrocardiograms recorded in groups of offspring from mothers with experimental SLE indicated that a high percentage of the offspring had defects in their conductive system including first-, second-, and third-degree heart block, significant bradycardia, and a wide QRS complex. In contrast, a normal pattern was observed in offspring of healthy mothers.

Animals↗
PubMed1994

Induction of experimental systemic lupus erythematosus in mice by immunization with the F(ab')2 fragment of the human anti-DNA monoclonal antibody carrying the 16/6 idiotype.

Induction of an experimental disease resembling murine systemic lupus erythematosus (SLE), has been achieved in mice by immunization with a human monoclonal anti-DNA antibody, bearing a common idiotype, designated 16/6 Id. In the present study we report the preparation of F(ab')2 proteolytic fragments of the human 16/6 Id mAb and the ability of the latter to induce experimental-SLE in mice. Following immunization with the F(ab')2 fragment, mice developed antibodies bearing the 16/6 Id, anti-16/6 Id and a variety of autoantibodies, similar to mice immunized with the whole 16/6 Id molecule. Serological manifestations of the disease such as leukopenia, proteinuria and renal damage, were developed following the immunization with the 16/6 Id F(ab')2 proteolytic fragments. These results demonstrate the pathogenic role of the F(ab')2 fragment that bears the 16/6 Id.

Animals↗
PubMed1994

Binding of glycoprotein 120 and peptides from the HIV-1 envelope by autoantibodies in mice with experimentally induced systemic lupus erythematosus and in patients with the disease.

Systemic lupus erythematosus (SLE) and infection with the human immunodeficiency virus type 1 (HIV) are diseases that are characterized by immune dysregulation and autoantibody production. In this article we identify and characterize IgG antibodies from mice with SLE and SLE patients that bind HIV gp120 and HIV envelope-derived peptides. SLE can be induced in susceptible mouse strains by immunization with a human monoclonal anti-DNA antibody that bears a common idiotype designated 16/6 Id. We tested sera from various strains of mice in which experimental SLE was induced by this method, as well as from 93 patients with SLE and 31 controls (17 healthy controls, 14 patients with other autoimmune diseases) for the presence of antibodies reactive to gp120 by an ELISA. Antibodies reactive with gp120 were produced by BALB/c, C3H.SW, AKR, and DBA/2 mice, all of which were 16/6 Id immunized and had experimental SLE. C57BL/6 mice, which are resistant to induction of SLE by this method, did not produce antibodies reactive with gp120 despite 16/6 immunization. Forty-three percent of SLE patients made antibodies that bound to gp120 at titers greater than 1:40, whereas 12% of healthy control sera (p < or = 0.02) and 14% of patients with other autoimmune diseases contained such antibodies (p < or = 0.05). We delineated the specificity of this antibody activity by testing for reactivity to six HIV envelope peptides. In both mice and SLE patients, sera reactive with gp120 recognized the same three envelope peptides. Removal of the anti-DNA antibodies from the sera by DNA-agarose affinity purification did not change anti-gp120 specificity.

Amino Acid Sequence↗
PubMed1994

Processing requirements of two acetylcholine receptor derived peptides for binding to antigen presenting cells and stimulation of murine T cell lines.

We have previously identified two myasthenogenic T cell epitopes of the human acetylcholine receptor (AChR) alpha subunit, peptides p195-212 and p259-271. These peptides were the immunodominant T cell epitopes of AChR in SJL and BALB/c mice respectively, and only cryptic in C3H.SW strain. In order to find out whether these mouse strains differ in their requirements for processing of the same T cell epitopes, we used p195-212 specific T cell lines from SJL, TCSJL195-212, and C3H.SW, TCSW195-212, mice, and p259-271 specific T cell lines from BALB/c, TCBALB/c259-271, and C3H.SW, TCSW259-271, mice. The peptide-specific proliferative responses of the lines TCSW195-212 and TCSW259-271, originated from strains in which these peptides are cryptic epitopes, were inhibited significantly in the presence of several inhibitors of proteases or glutaraldehyde-fixed antigen presenting cells (APC). In contrast, the proliferative responses of the lines TCSJL195-212 and TCBALB/c259-271, established from strains in which these peptides are immunodominant, were only slightly affected by the above inhibitors or by fixation of the APC. Using a direct binding assay of biotinylated peptides to live intact APC, we showed that peptides p195-212 and p259-271 preserved their binding capacity to APC of SJL and BALB/c mice respectively when processing was inhibited. Thus, the AChR peptides that represent cryptic T cell epitopes have to be processed before they can be recognized by T cells, whereas no further processing is necessary for APC presentation and T cell stimulation when these peptides are immunodominant epitopes.

Amino Acid Sequence↗
PubMed1994

An autoantibody derived from mice with experimental systemic lupus erythematosus is directed against the essential splicing factor SF53/4--a possible role for large nuclear ribonucleoprotein particles in autoimmune disorders.

We have previously shown that nuclear transcripts of several pre-mRNAs can be released from nuclei of mammalian cells in a form of large nuclear ribonucleoprotein (InRNP) particles. These particles, which invariably sediment at the 200S region in sucrose gradient, contain all U small nuclear RNPs required for pre-mRNA splicing and a multitude of heterogeneous nuclear RNP proteins. From a panel of mAbs raised against the InRNP particles, a specific mAb (53/4) identified a nuclear protein of 88 kDa as an essential splicing factor (SF53/4). In a parallel independent study, mAbs were established in mice with experimental systemic lupus erythematosus (SLE), that had been induced by immunization with a murine mAb against a human anti-DNA mAb bearing the common 16/6 idiotype. One of the produced mAbs (2C5/3) recognized an 88 kDa RNP protein. In the present study we have used the following criteria to demonstrate that mAb 2C5/3 and mAb 53/4 recognize the same protein. First, mAb 2C5/3 inhibited splicing by direct addition. Second, the 88 kDa polypeptide that had been immunodepleted from HeLa cells nuclear extract by mAb 2C5/3 was recognized by mAb 53/4 in protein blots. Third, the HeLa nuclear extract depleted by mAb 2C5/3 was devoid of splicing activity and could not assemble into splicing complexes with exogenous pre-mRNA; however, splicing and spliceosome assembly activities were restored to such a defective extract by adding back the 88 kDa protein that had been purified by immunoaffinity binding to immobilized mAb 53/4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Inhibition of autoantibody production in experimental SLE by pre-immunization with DNA.

Experimental SLE can be induced in susceptible mice by their immunization with the human monoclonal anti-DNA antibody that bears a major idiotype-16/6 Id. The SLE afflicted mice produce a variety of autoantibodies including anti-DNA antibodies. It was of interest to find out the effect of DNA on the induction of the experimental disease. To this end, mice were immunized with combinations of 16/6 Id and DNA. The results indicated that whereas mice primed with 16/6 Id developed high titers of antibodies to the 16/6 Id and a variety of autoantibodies typical to the experimental SLE, preimmunization of mice with ssDNA led to a reduction in the 16/6 Id specific antibodies and in the autoantibody titers. No significant differences could be detected in the clinical manifestations which are present in the mice with experimental disease (increased erythrocyte sedimentation rate, leukopenia, proteinuria and glomerular immune complex deposition) in all mice immunized with 16/6 Id including those pretreated with DNA. Thus, no direct correlation exists between the autoantibody levels and the clinical pathology, and probably other factors are involved in the development of the experimental disease.

Animals↗
PubMed1994

The beneficial effect of the estrogen antagonist, tamoxifen, on experimental systemic lupus erythematosus.

OBJECTIVE: To determine the effects of the estrogen antagonist, tamoxifen, on the development and the course of experimental murine systemic lupus erythematosus (SLE). METHODS: SLE was induced in naive BALB/c female mice by injection of the human monoclonal anti-DNA antibody bearing the 16/6 idiotype (Id). Six weeks following immunization, when high levels of autoantibodies were demonstrated, the mice were treated with tamoxifen (200-800 micrograms/mouse twice a week) up to a period of 8 months. In several mouse groups tamoxifen treatment was started as late as one year following the immunization with the 16/6 Id when overt disease was already observed. RESULTS: Tamoxifen treatment had no effect on the 16/6 Id induced autoantibody production. However, the 16/6 Id immunized and tamoxifen treated mice demonstrated normal numbers of white blood cells (WBC) and thrombocytes while the untreated groups had significant leukopenia and thrombocytopenia. Similarly, persistent proteinuria and immune complex deposits in the kidneys were observed in the 16/6 Id immunized mice whereas no such deposits were found in kidney sections of 16/6 Id immunized mice that were treated with tamoxifen. Delayed tamoxifen treatment (starting a year following the immunization) also demonstrated beneficial therapeutic effects. CONCLUSION: These studies demonstrate therapeutic effects of tamoxifen on murine experimental SLE suggesting a possible role for this estrogen antagonist in the treatment of human SLE and related disorders.

Animals↗
PubMed1993

Inhibition of T-cell reactivity to myasthenogenic epitopes of the human acetylcholine receptor by synthetic analogs.

The synthetic peptides p195-212 and p259-271, representing amino acids 195-212 and 259-271 of the alpha subunit of the human acetylcholine receptor, preferentially stimulate T cells of patients with myasthenia gravis and are immunodominant T-cell epitopes in SJL and BALB/c mice, respectively. We designed and synthesized analogs of these peptides that contain single amino acid substitutions. An analog of peptide p195-212, no. 455 (Met-207-->Ala), was capable of inhibiting up to 100% of the proliferative responses of a p195-212-specific T-cell line originating from the high-responder strain SJL. Similarly, an analog of p259-271, no. 306 (Glu-262-->Lys), was capable of inhibiting up to 93% of the proliferative responses of the p259-271-specific T-cell line originating from high-responder BALB/c mice. Analog 306 also inhibited up to 43% of the proliferative responses of p259-271-primed lymph node cells in an in vitro proliferation assay. To test the in vivo inhibitory activity of the analogs, mice were primed with the myasthenogenic peptides in complete Freund's adjuvant concomitant with administration of the analogs in aqueous solution. Administration of analogs 455 and 306 led to decreased proliferative responses of up to 70% by peptide p199-212-primed lymph node cells and up to 85% by peptide p259-271-primed lymph node cells. Similar results were obtained whether the analogs were administered i.v. or i.p. Thus, these analogs are good candidates for specific immunomodulatory therapy for patients with myasthenia gravis.

Amino Acid Sequence↗