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E Mozes

Publications and source records attributed to E Mozes.

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

Genetic analysis of experimentally induced lupus in mice.

The DBA/2 and C57BL/6 mouse strains, as well as the BXD RI lines derived from these strains, were used to map the genes controlling experimentally induced systemic lupus erythematosus (SLE). SLE was induced using two immunologic approaches: (1) immunization with the human monoclonal anti-DNA antibody expressing the 16/6Id, to which the DBA/2 strain is susceptible (responder) and the C57BL/6 strain is resistant (nonresponder); and (2) induction of autoimmune GVHD in B6D2F1 hosts by inoculation of parental DBA/2 (induces SLE) or C57BL/6 (does not induce SLE) T cells. By both approaches the BXD RI lines could be divided into distinct DBA/2-like and C57BL/6-like categories. Concordance of SLE induced by both methods was observed for susceptibility and resistance in 13/15 BXD lines (P < 0.005). The results suggest that at least two non-H-2 genes control susceptibility and resistance to experimentally induced SLE, one mapping to chromosome 7 and the other mapping to chromosome 14.

Animals↗
PubMed1997

Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus afflicted mice.

The objective of the this study was to determine the cytokine profile of aging mice and to establish whether changes in cytokine production account for the fact that aging mice develop a milder disease than the young in response to induced experimental systemic lupus erythematosus (SLE). Cytokine secretion was evaluated in groups of BALB/c and C3H.SW mice at different ages between 2 and 24 months. The production of IL-2, IL-4, IL-10, IFN gamma and TNF alpha was determined in supernatants of ConA-stimulated splenocytes and that of IL-1 in the supernatants of LPS-stimulated peritoneal macrophages. A gradual age-related decline was observed in the production of IL-2 and IFN gamma, whereas the levels of IL-4, IL-10, IL-1 and TNF alpha progressively increased with aging, in unimmunized BALB/c and C3H.SW mice. Experimental SLE was induced in 2 and 10 month old C3H.SW mice by immunization with the monoclonal anti-DNA antibody bearing the 16/6 Id. The characteristic cytokine profile following immunization of 2 month old mice was early increased production of TNF alpha and IL-1, followed by a peak of Th1 type cytokines (IL-2, IFN gamma). At a later stage of the disease, a peak of Th2 type cytokines (IL-4, IL-10) was observed that was concomitant with low levels of Th1 cytokines. In contrast, in the 10 month old mice that were immunized with 16/6 Id only a mild increase in all the above cytokines was observed. We suggest that the lower autoantibody production and moderate clinical manifestations in aging mice with experimental SLE are causally related to the decreased production of pro-inflammatory cytokines at the initial stages of the disease followed by a lower production of both Th1 and Th2 type cytokines.

Aging↗
PubMed1997

The beneficial effects of treatment with tamoxifen and anti-oestradiol antibody on experimental systemic lupus erythematosus are associated with cytokine modulations.

In an attempt to elucidate the role of oestrogens in systemic lupus erythematosus (SLE) we investigated the effects of treatment with an oestrogen antagonist-tamoxifen and a monoclonal anti-oestradiol (anti-E2) antibody on mice in which experimental systemic lupus erythematosus (SLE) was induced by a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id). Thus, groups of BALB/c female mice were immunized with the 16/6 Id and 3 weeks following the booster injection, when antibody titres were elevated in the injected mice, treatment protocols with anti-oestradiol or tamoxifen were initiated. Control groups that were not immunized with the 16/6 Id but were similarly treated with the above agents were included in the study. The treatment with the above agents had no effect on the total autoantibody titres; however, a decrease in the immunoglobulin G (IgG)2a/IgG1 ratio of the anti-DNA antibodies was determined in the 16/6 Id immunized and treated mice. Further both the anti-oestradiol and tamoxifen had beneficial effects on the clinical manifestations (white blood cell counts, levels of protein in the urine and immune complex deposits in the kidneys) of the 16/6 Id immunized and treated mice. We have previously observed a significant elevation in interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) secretion in mice with experimental SLE and a reduction in IL-2, IL-4 and interferon-gamma (INF-gamma) levels as compared with the levels detected in healthy controls. Treatment with either the anti-oestradiol antibody or with tamoxifen restored the levels of all the above cytokines to the normal levels observed in the control mice. These findings suggest that cytokine modulation may be the basis for the therapeutic effects of both anti-oestrogens in experimental SLE.

Animals↗
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

Cytokine manipulation by methotrexate treatment in murine experimental systemic lupus erythematosus.

OBJECTIVE: We reported beneficial effects of methotrexate (MTX) treatment on clinical variables in the murine model of experimental systemic lupus erythematosus (SLE). We now follow the kinetics of several cytokines that are involved in experimental SLE, to find out whether MTX treatment has an effect on cytokine production. METHODS: SLE was induced in naive BALB/c female mice by injection of the human monoclonal anti-DNA antibody bearing the common idiotype, 16/6 Id. Six weeks after booster injection, when high levels of autoantibodies were observed, MTX treatment was started (2 mg/kg once a week) for 7 months. Cytokine production by macrophages or splenocytes from these mice was determined monthly by either ELISA or bioassays. RESULTS: A significant increase in the production of tumor necrosis factor-alpha was determined as early as 2 weeks after injection. Interleukin 1 (IL-1) production increased gradually, starting one month after disease induction. These proinflammatory cytokines reached very high levels that were maintained through disease course. MTX treatment reduced production of these cytokines to normal levels throughout the experimental period. Increased levels of IL-2 and interferon-gamma (IFN-gamma), the Th1 type cytokines, were detected 2-4 months after disease induction. The secretion of the latter then dropped to levels lower than those observed in control mice. Treatment with MTX reversed levels of the cytokines to levels observed in healthy mice, IL-4 and IL-10, the Th2 type cytokines, predominated later in disease course, 5 months after immunization. Two to 3 months later production of IL-4 dropped to levels lower than those of control mice. IL-10 secretion remained higher than in controls throughout the experiment. The production of both IL-4 and IL-10 in MTX treated mice was also similar to that of control mice. CONCLUSION: The restoration of the cytokine profile to normal levels observed in the MTX treated mice from the initial steps of disease induction suggests its beneficial effects in SLE might be mediated through modulation of cytokine production.

Animals↗
PubMed1997

Role of MHC class I molecules in autoimmune disease.

The MHC class I molecules play a pivotal role in triggering cellular immune responses, binding and presenting intracellularly derived peptide antigens. Studies of MHC class I expression revealed a complex regulatory mechanism that integrates tissue-specific and hormonal modulation. Dynamic regulation occurs in the thyroid, in response to hormonal repression by TSH and stimulation by thyroid hormone. This dynamic cycle provides the basis for proposing the model that such regulation is important to maintain tolerance to self-antigens in tissues synthesizing large amounts of secretory proteins. Failure to appropriately regulate class I levels is predicted to result in autoimmunity. In support of this model, we found that class I-deficient mice are resistant to the experimentally induced autoimmune diseases, SLE, and blepharitis. Furthermore, pharmacological treatment with an agent that reduces class I expression also reduces the incidence and severity of both experimental and spontaneous autoimmune SLE.

Animals↗
PubMed1996

MHC class II-mediated T cell response to DNA.

Anti-DNA antibodies are elevated in several autoimmune diseases, including systemic lupus erythematosus. Yet, DNA was not shown to be presented by molecules of the major histocompatibility complex (MHC), nor was it reported to specifically stimulate T cells in vivo, although these steps are essential for antibody production. We now demonstrate DNA-specific T cell activation, which involves presentation of DNA by MHC class II molecules. T cells, isolated from lymph nodes of mice immunized with a murine monoclonal anti-anti-DNA antibody, proliferated in response to DNA. Moreover, presentation of DNA by murine antigen-presenting cells could be inhibited with an isotype-specific anti-Ia antibody, and with peptides restricted by the same H-2 haplotype, suggesting that it is MHC class II-mediated. These results indicate that DNA can play a direct role in the regulation of T cells and in autoimmune processes.

Animals↗
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

Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse.

Targeted disruption of the transforming growth factor-beta 1 (TGF-beta 1) gene in mice results in the development of a massive multifocal inflammatory disease in many tissues. Because no detectable pathogen was identified, we examined whether autoimmune mechanisms played a role in initiating or maintaining the inflammatory disease. The serum of TGF-beta 1 knockout mice contained elevated titers of antibodies to nuclear antigens (ssDNA, dsDNA, Sm, and RNP) as well as reactivity against the 16/6 idiotype (16/6 Id). In addition, Ig deposits were detected in renal glomeruli of TGF- beta 1 knockout mice. Transplantation of TGF-beta 1 knockout hematopoietic cells into normal irradiated recipients resulted in a similar profile of autoantibody production as well as in the induction of inflammatory lesions. Our results describe autoimmune activity that ensues when the TGF-beta 1 cytokine is absent.

Animals↗
PubMed1996

Effect of injection of anti-CD4 and anti-CD8 monoclonal antibodies on the development of experimental systemic lupus erythematosus in mice.

Induction of an experimental disease resembling 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 used anti-CD4 and anti-CD8 antibodies to modulate the induction and development of the experimental disease. Thus, depletion of CD4+ T cells prior to the immunization with the 16/6 inhibited the induction of experimental SLE. In contrast, injection of anti-CD4 antibodies to mice that were already immunized with the 16/6 Id did not prevent the development of the disease. Furthermore, administration of anti-CD8 antibodies either before or after priming with the 16/6 Id increased the serological and clinical manifestations of the disease. These results demonstrate the pathogenic role of CD4+ and CD8+ T cells in the induction and development of the experimental SLE.

Animals↗
PubMed1996

Amelioration of experimental systemic lupus erythematosus (SLE) by retrovirus infection.

Experimental SLE can be induced in susceptible 129/J mice by immunization with a human anti-DNA antibody bearing a common idiotype designated 16/6 Id. Immunized mice develop autoantibodies, leukopenia, proteinuria, and immune complex deposits in renal glomeruli. Case reports have described clinical improvement in SLE in individuals becoming infected with HIV-1. Because 129/J mice are susceptible to experimental SLE and to infection with the BM5def murine leukemia virus (MuLV) mixture but do not develop the lymphoproliferative/ immunodeficiency disorder known as murine AIDS (MAIDS), we superimposed this infection on immunization with the 16/6 Id. Multiple effects were observed. First, we noted an amelioration in the course of experimental SLE. Second, both in experimental SLE and in BM5def MuLV infection, immunoreactivity to HIV-1 gp120 was demonstrated, although gp120 is not present in the BM5def MuLV viruses. Third, production of autoantibodies characteristically found in SLE, e.g., anti-DNA, anti-RNP, and anti-SSA, was seen in BM5def MuLV-infected mice, demonstrating that an immune response as a consequence of infection had occurred despite the absence of MAIDS induction. We conclude that (1) retrovirus inoculation may ameliorate the course of experimental SLE; and (2) retrovirus inoculation, even in the absence of MAIDS induction, induces an immunologic response which promotes the production of potentially pathogenic autoantibodies.

Animals↗
PubMed1996

Anticardiolipin, but not the 16/6 Id anti-DNA antibody induces pregnancy failure.

The primary antiphospholipid syndrome or the antiphospholipid syndrome in systemic lupus erythematosus patients (defined as secondary antiphospholipid syndrome) are characterized by the presence of thrombosis, thrombocytopenia and recurrent fetal loss in association with anticardiolipin antibodies. To determine the causal role of these antibodies in the pathogenesis of pregnancy failure we studied the effects of immunization with monoclonal anti-DNA antibody (designated 16/6 Id; no cardiolipin reactivity) and anticardiolipin monoclonal antibody (designated 2C4C2; binds DNA as well) on the outcome of allogeneic pregnancies in BALB/c mice. Mating of BALB/c females 4 weeks after active immunization with the 16/6 Id, anti-DNA monoclonal antibody resulted in normal pregnancy outcome, similar to control mouse groups. In contrast to that, immunization with the 2C4C2 anticardiolipin antibodies resulted in severe gestational failure with low pregnancy rate, low numbers of fetuses and high rates of resorptions. The fertility index of those mice was extremely low as compared to the 16/6 Id-immunized mice or the control groups. Furthermore, a correlation was shown between the presence of anticardiolipin antibody levels in the sera of the mice at the time of gestation and the pregnancy fate. The 2C4C2-immunized mice which produced high levels of anticardiolipin antibodies demonstrated severe pregnancy failure, whereas normal gestations were observed in the 16/6 Id primed or the control mouse groups that did not produce measurable amounts of the latter antibodies. Thus, our studies demonstrate that anticardiolipin but not the 16/6 Id anti-DNA antibodies can induce severe gestational impairment.

Abortion, Spontaneous↗
PubMed1996

Altered peptide ligands of a myasthenogenic epitope as modulators of specific T-cell responses.

Myasthenia gravis (MG) is a T-cell regulated autoimmune disease. A peptide representing a sequence of the human acetylcholine receptor alpha-subunit (p195-212) was previously shown to stimulate proliferative responses of peripheral blood lymphocytes from MG patients and to be an immunodominant and myasthenogenic T-cell epitope in SJL mice. The authors generated a panel of analogues of p195-212 that contain single amino acid substitutions. Three of the analogues (203PHE, 204GLY and 207ALA) triggered low to no proliferative responses of a p195-212-specific T-cell line designated TCSJL195-212. Two of these analogues were able to stimulate the line to produce interleukin-2 (IL-2) and IL-4 (203PHE and 204GLY), whereas one analogue, 207ALA, did not stimulate the line to produce these cytokines. Binding assays revealed that the binding affinity of an altered peptide for a given major histocompatibility complex (MHC) molecule is not sufficient to determine whether it will be stimulatory or inhibitory to a native peptide-specific T-cell line. Two of the analogues, 204GLY and 207ALA, inhibited proliferative responses of cells of the TCSJL195-212 line when co-cultured with p195-212 and syngeneic antigen presenting cells (APC). The two inhibitory analogues were also able to inhibit proliferative responses of the TCSJL195-212 line when APC were pre-pulsed with p195-212, indicating that MHC blockade is not the only mechanism of action of these peptides. Moreover, both analogues inhibited the ability of p195-212 to prime lymph node cells for proliferative responses even when the analogues were administered in a soluble form. Thus the altered peptide ligands 207ALA and 204GLY can modulate T-cell responses both in vitro and in vivo and may have therapeutic potential for the treatment of MG.

Amino Acid Sequence↗
PubMed1996

Defective maternal-fetal interaction in a murine autoimmune model.

Anti-cardiolipin antibodies (ACA) are associated with recurrent fetal loss, but their role in this pathological condition is unknown. We recently developed an experimental mouse model of the anti-phospholipid syndrome, in which immunization of female mice with a monoclonal anti-cardiolipin antibody resulted in substantial failure of pregnancy. We observed that pre-implantation embryos derived from ACA-injected mothers exhibited morphological abnormalities and failed to implant in vitro. In the present study, we designed embryo transfer experiments to determine whether defective embryonic development originated as a maternal defect, an embryonic defect or both. Embryos (3.5 day old), taken from ACA- and control-immunized mothers were transferred into either an ACA- or a control-treated uterine environment (day 2.5 pseudopregnant females). On day 14 of gestation the incidence of pregnancy, the average number of fetuses per female and fetal resorptions were assessed. The ACA-treated uterine environment was found to be non-supportive for the development and implantation of normal embryos. Moreover, embryos derived from ACA-immunized mothers, even after their removal from the ACA-environment and transfer to a normal uterus, remained deficient. These results demonstrate that both the maternal and the embryonic compartments were defective, as a result of previous exposure to the ACA.

Animals↗
PubMed1996

Variable regions of two murine antibodies that bind the SLE associated 16/6 idiotype.

Experimental systemic lupus erythematosus can be induced in naive mice of different strains using a human monoclonal antibody bearing the 16/6 idiotype and a murine anti-16/6 Id monoclonal antibody designated 1A3-2. Herein we report the isolation of a second anti-16/6 Id antibody, 3F7-8, from BALB/c mice afflicted with experimental SLE. In contrast to the previously reported (1A3-2) anti-16/6 Id monoclonal antibody, mAb 3F7-8 does not induce experimental SLE upon immunization. The variable heavy and light chains of both antibodies were cloned and their sequences were determined. The VH of mAb 1A3-2 was found to express a germ line gene from the Q52 family, with a high homology to an anti-lysozyme antibody. The VH of monoclonal antibody 3F7-8 was found to express a 7183 germ line gene, showing over 95% homology with the VH of 12 anti-Sm antibodies isolated from MRL-lpr mice. Based on sequence homology to other known antibodies, we further demonstrated that monoclonal antibodies 1A3-2 and 3F7-8 bind lysozyme and the Sm ribonucleoproteins, respectively, in addition to their binding to the 16/6 Id.

Amino Acid Sequence↗
PubMed1995

Detection of antigens in immune complexes by a dot blot assay.

A simple assay is described for detection of antigens as a part of immune complexes. The complexes together with free IgG molecules are absorbed on protein A (or G)-Sepharose. The Sepharose beads are transferred to nitrocellulose membrane where all IgG including their complexes with antigens are eluted by acidic buffer directly on the surface of the membrane. The antigens immobilized on the membrane after elution are detected by corresponding labeled antibodies. The validity of the procedure was assessed by experiments with complexes of avidin and rabbit antibodies. The assay was used also for detection of DNA in immune complexes in mice with experimental systemic lupus erythematosus (SLE).

Animals↗
PubMed1995

Periocular inflammation in mice with experimental systemic lupus erythematosus. A new experimental blepharitis and its modulation.

Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human monoclonal anti-DNA Ab, bearing a major Id 16/6Id. Immunized mice initially produce Abs to 16/6Id, DNA and nuclear Ags, and subsequently develop various clinical manifestations including leukopenia and renal immune complex disease. MHC class I Ags play a critical role in the induction and progression of experimental SLE. The present study reports that ocular changes also occur in mice with experimental SLE. The ocular disease is characterized by bilateral subacute and chronic inflammation of the eyelids (blepharitis) with immune complex IgG deposition and hypertrophic meibomian glands. The severity of ocular changes was strain dependent: most severe in 129 mice, less intense in BALB/c animals and only minimal in C3H.SW mice. No blepharitis developed in mice deficient in MHC class I expression. Further, the disease was strongly inhibited in BALB/c mice treated with methimazole, an agent that has been shown to repress transcription of MHC class I. In these cases, there was no IgG deposition and a decreased infiltration of inflammatory cells in the eyelids. These observations thus suggest that, similar to the observation with experimental SLE, MHC class I is critical in the onset of this experimental autoimmune blepharitis. The new experimental eye disease described here provides an animal model for chronic blepharitis in humans, a common condition for which such a model has been sought.

Animals↗