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Biomedical subjects

M Dayan

Publications and source records attributed to M Dayan.

At least 19 recordsLinked to original sources
PubMed1999

DNA levels in immune complexes circulating in mice with induced systemic lupus erythematosus.

The levels of DNA in IgG immune complexes, which appeared in the circulation of mice after the induction of systemic lupus erythematosus (SLE), were measured by an immunochemical quantitative assay using monoclonal anti-dsDNA antibodies. The amount of DNA in immune complexes was already high at 10-12 days following the injection of a human monoclonal anti-DNA antibody bearing the major idiotype designated 16/6 in complete Freund's adjuvant, i.e. long before the appearance of clinical manifestations. The injections of these antibodies in the alum-precipitated form did not induce the formation of DNA:anti-DNA complexes as well as SLE itself. The levels of DNA in circulating immune complexes were in general high throughout the whole experimental period (up to 7 months) decreasing gradually before the first clinical manifestations appeared and thereafter, when the disease was fully developed. Such a decrease could be explained by the retention of immune complexes in kidneys. The levels of DNA in immune complexes circulating in normal mice or in mice receiving injections of complete Freund's adjuvant was very low. Treatment of experimental SLE that affected the clinical manifestations prevented the formation of high levels of DNA containing immune complexes.

Animals↗
PubMed1998

Single amino acid analogs of a myasthenogenic peptide modulate specific T cell responses and prevent the induction of experimental autoimmune myasthenia gravis.

Peptide p259-271 of the human acetylcholine receptor alpha-subunit, preferentially stimulates T cells of patients with myasthenia gravis (MG) and is an immunodominant epitope for T cells of BALB/c mice. A p259-271 specific T cell line of BALB/c origin was established and was shown to induce experimental MG in naive mice. Seven analogs of p259-271 were synthesized, and two of them were found to inhibit the p259-271 specific proliferative responses of the line and of p259-271 primed lymph node cells. Moreover, the most efficient inhibitor, analog 262Lys, prevented the MG related manifestations in mice inoculated with the line, and might be of potential value for the treatment of MG.

Amino Acid Sequence↗
PubMed1998

A novel method for the determination of T-cell proliferative responses in patients with uveitis.

Standard proliferation assays using autoantigens such as S-Ag have given erratic responses when studied with human peripheral blood mononuclear cells. This erratic response is a reflection of the low number of circulating cells in the peripheral blood capable of generating a response as well as the presence of competing cells for the available cytokines in culture. The present study compares the standard proliferation assay with a novel technique in which multiple short-term cell lines are established to S-Ag in medium enriched in helper cytokines. After 12-14 days of culture, these lines were tested for their response to S-Ag. A significant difference was found between patients and controls in the ability to generate responsive cell lines. This translated to a frequency of responsive cells of 0-4 per 10(7) peripheral blood mononuclear cells (PBMC) in normal individuals and 0-200 per 10(7) PBMC in patients. This novel technique may provide a means of determining the number of responsive cells to specific autoantigens in the peripheral blood of patients and the ability to follow the response over time.

Antigen-Presenting Cells↗
PubMed1997

Modulation of murine systemic lupus erythematosus with peptides based on complementarity determining regions of a pathogenic anti-DNA monoclonal antibody.

Experimental systemic lupus erythematosus (SLE) can be induced in naive mice by immunization with a murine monoclonal anti-DNA antibody (mAb), 5G12, that bears a major idiotype designated 16/6 Id. Strain-dependent differences were observed in the proliferative responses of lymph node cells of mice immunized with two peptides based on the sequences of the complementarity determining region (CDR) 1 and 3 of mAb 5G12. The capacity of the peptides to bind to major histocompatibility complex class II molecules correlated with the proliferative responses. Immunization of high responder strains with the CDR-based peptides led to production of autoantibodies and clinical manifestations characteristic to experimental SLE. The CDR-based peptides could prevent autoantibody production in neonatal mice that were immunized later either with the peptide or with the pathogenic autoantibody. Furthermore, the peptides inhibited specific proliferation of lymph node cells of mice immunized with the same peptide, with mAb 5G12 or with the human mAb anti-DNA, 16/6 Id. Thus, the CDR-based peptides are potential candidates for therapy of SLE.

Amino Acid Sequence↗
PubMed1997

A peptide composed of tandem analogs of two myasthenogenic T cell epitopes interferes with specific autoimmune responses.

Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor alpha-subunit, p195-212 and p259-271, were previously shown to stimulate peripheral blood lymphocytes of patients with MG and were found to be immunodominant T cell epitopes in SJL and BALB/c mice, respectively. Single amino acid substituted analogs of p195-212 (analog Ala-207) and p259-271 (analog Lys-262) were synthesized. We showed that analogs Ala-207 and Lys-262 inhibited, in vitro and in vivo, the proliferative responses of T cell lines specific to the relevant peptide and lymph node cells of mice immunized to p195-212 and p259-271, respectively. To inhibit T cell responses to both peptides (p195-212 and p259-271), we synthesized dual analogs composed of the tandemly arranged two single (Ala-207 and Lys-262) analogs (dual analog) either sequentially (Ala-207-Lys-262) or reciprocally (Lys-262-Ala-207). In the present study, we report that both dual analogs could bind to major histocompatibility complex class II molecules on antigen-presenting cells of SJL and BALB/c mice. Analog Lys-262-Ala-207, which bound more efficiently to major histocompatibility complex class II molecules, was found to inhibit the proliferative responses of both p195-212- and p259-271-specific T cell lines. Furthermore, the analog inhibited the in vivo priming of lymph node cells of both SJL and BALB/c mice when administered i.v., i.p., or per os. The dual analog Lys-262-Ala-207 could also immunomodulate myasthenogenic manifestations in mice with experimental autoimmune MG induced by inoculation of a pathogenic T cell line. Thus, a single peptide that is composed of analogs to two epitope specificities can be used to regulate T cell responses and disease associated with each epitope.

Amino Acid Sequence↗
PubMed1997

Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease.

We followed cytokine production from induction through disease progression in a murine model of experimental systemic lupus erythematosus (SLE). SLE was induced by immunization with the human monoclonal anti-DNA Ab that bears the common Id designated 16/6 Id. BALB/c and C3H.SW mice that are susceptible to SLE induction and C57BL/6 mice that are resistant were immunized with the 16/6 Id. Cytokine production was tested periodically for 7 mo. Increased production of IL-2 and IFN-gamma, the Th1-type cytokines, was detected in BALB/c and C3H.SW mice 2 to 4 mo following immunization. IL-4 and IL-10, the Th2-type cytokines predominated later in disease course, and peaked 5 mo following disease induction. At this stage the Th1 type cytokines dropped to levels below those observed in controls. IL-4 production also dropped rapidly to very low levels, while IL-10 production decreased but remained above control levels. The ratio of IgG2a/IgG1 of DNA and 16/6 Id-specific Abs peaked at 2 mo following disease induction and decreased later, in concordance with the higher production of Th2-type cytokines. Thus, the development of experimental SLE in mice involves two stages: increased production of Th1-type, followed by increased induction of Th2-type cytokines. High levels of the proinflammatory cytokines, TNF-alpha and IL-1, were maintained throughout disease course. No significant changes were detected in the cytokine profile of C57BL/6 immunocytes following immunization with the 16/6 Id, supporting the possible role of the cytokine network in SLE.

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 effectiveness of topical diclofenac in relieving discomfort following traumatic corneal abrasions.

Diclofenac is a non-steroidal anti-inflammatory drug available in an ophthalmic preparation. We present a prospective randomised double-masked placebo-controlled trial involving 40 patients that assessed the effectiveness of topical diclofenac in relieving pain from traumatic corneal abrasions. Statistical analysis of visual analogue and categorical pain scores revealed a significant reduction in pain experienced by subjects in the diclofenac group (p < 0.02).

Administration, Topical↗
PubMed1997

The role of staphylococcal superantigens in the pathogenesis of marginal keratitis.

Previous studies have demonstrated an increased incidence of delayed-type hypersensitivity to staphylococcal antigens in patients with blepharitis, but this does not predict subsequent development of marginal keratitis (MK). Superantigens are potent immune-modifying molecules produced by pathogenic organisms including Staphylococcus aureus. To study whether staphylococcal superantigens play a role in the development of MK, conjunctival and lid margin cultures were taken from 26 subjects with MK and 24 controls. Four of 8 eyes with their first episode of MK grew strains of S. aureus, of which only one was superantigen-producing. None of the subjects with recurrent MK and only one control grew S. aureus. We conclude that staphylococcal superantigens are unlikely to play a central role in the development of MK. The absence of S. aureus on the lids of subjects with recurrent MK may reflect an alteration in lid flora due to previous topical antibiotic and steroid treatment.

Conjunctiva↗
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↗
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↗