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Biomedical subjects

M Dayan

Publications and source records attributed to M Dayan.

At least 19 recordsLinked to original sources
PubMed2005

Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of autoantibodies directed against an epitope of the glutamate/N-methyl-D-aspartic acid (NMDA) receptor subunit NR2A (which is highly expressed in human brain) in the sera of lupus patients, and to investigate the possible correlation of these antibodies with clinical and serological manifestations of systemic lupus erythematosus (SLE). METHODS: Sera were obtained from 109 consecutive SLE patients. Controls were 65 patients with myasthenia gravis, 19 with autoimmune polyendocrine syndrome type I (APS I), and 65 healthy donors. A 15 amino acid long peptide based on a sequence within the NR2A subunit of the NMDA/glutamate receptor was synthesised. Antibodies to this peptide were determined by enzyme linked immunosorbent assay. Antibodies against double stranded DNA (dsDNA) were measured by Chrithidia luciliae assay. Disease activity was determined using the SLE disease activity index (SLEDAI). RESULTS: Sera of 34/109 SLE patients (31%) reacted specifically with the NR2A peptide compared with only 4/65 myasthenia gravis patients (6.1%, p<0.001), 1/19 APS I patients (5.3%, p<0.02), and 3/65 healthy controls (4.6%, p<0.001). No correlation was found between the presence of NR2A and dsDNA or anti-cardiolipin specific autoantibodies. In addition, no significant correlation was observed between the presence of NR2A specific antibodies and the SLEDAI score or any lupus related clinical manifestations. CONCLUSIONS: A significant number of SLE patients (31%) have NR2A specific antibodies that do not correlate with anti-dsDNA antibodies. Additional studies of lupus patients with neurological disorders should elucidate the role of NR2A specific antibodies in lupus related CNS manifestations.

Adult↗
PubMed2004

Use of colour duplex ultrasound to diagnose giant cell arteritis in a case of visual loss of uncertain aetiology.

Giant cell arteritis is a common condition that can result in permanent visual loss. It has traditionally been diagnosed by invasive temporal artery biopsy in cases of clinical suspicion. The findings of colour duplex ultrasound have recently been described. We report the use of duplex ultrasound to diagnose temporal arteritis, with clinicopathological correlation, and discuss the possible application of this non-invasive technique to the management of giant cell arteritis.

Aged↗
PubMed2003

Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies.

Two peptides, based on the sequences of the complementarity-determining regions (CDR) 1 and 3 of a pathogenic murine monoclonal anti-DNA autoatibody that bears the 16/6 idiotype (Id), were shown to either prevent or treat an already established systemic lupus erythematosus (SLE) in two murine models of lupus. Two additional peptides based on the human monoclonal anti-DNA, 16/6 Id were synthesized. This study was undertaken in order to investigate the ability of the CDR-based peptides to immunomodulate SLE-associated responses of peripheral blood lymphocytes (PBL) of SLE patients. PBL of 24 of the 62 SLE patients tested proliferated in vitro following stimulation with the human 16/6 Id. Peptides based on the CDRs of both the human and murine anti-DNA autoantibodies inhibited efficiently and specifically the 16/6 Id-induced proliferation and IL-2 production. The latter inhibitions correlated with an up-regulated production (by 2.5-3.5-fold) of the immunosuppressive cytokine, TGF-beta. Overall, the results of our study demonstrate that the CDR-based peptides are capable of down-regulating in vitro autoreactive T cell responses of PBL of SLE patients. Thus, these peptides are potential candidates for a novel specific treatment of SLE patients.

Adolescent↗
PubMed2002

Activity of matrix metalloproteinase-9 is elevated in sera of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of autoantibodies and by systemic clinical manifestations and damage to multiple organs. The aim of the present study was to analyse matrix metalloproteinase (MMP)-9 activity in sera of patients with active and inactive SLE in order to evaluate its role in the pathogenesis and course of the disease, as well as its diagnostic value. We measured activity levels of MMP-9 and MMP-2, using both gel zymography and activity assay kits, in sera of 40 SLE patients and of 25 healthy controls. We found that MMP-9 activity, but not MMP-2 activity, is significantly elevated in the sera of SLE patients compared with sera samples of healthy controls. High activity levels of MMP-9 were determined in sera of 68% of the SLE patients. Elevated levels of MMP-9 were correlated with the presence of discoid rash, Raynaud phenomenon, pneumonitis, mucosal ulcers and anti-phospholipid antibodies. Changes in activity levels of MMP-9, but not of MMP-2, were observed in sera of the same patient at different periods of the disease course. High levels of MMP-9 did not correlate with disease activity index (SLEDAI, BILAG) in female patients, but correlated with SLE activity in the group of male patients. The results of the present study suggest that MMP-9 plays a role in the pathogenesis of SLE.

Adolescent↗
PubMed2001

The mechanism by which a peptide based on complementarity-determining region-1 of a pathogenic anti-DNA auto-Ab ameliorates experimental systemic lupus erythematosus.

A peptide based on complementarity-determining region (CDR)-1 of a monoclonal murine anti-DNA Ab that bears the common idiotype, 16/6Id, was synthesized and characterized. The peptide, designated pCDR1, was found to be an immunodominant T-cell epitope in BALB/c mice. The CDR1-based peptide was shown to be capable of inhibiting the in vivo priming of BALB/c mice immunized with the peptide or with the whole anti-DNA 16/6Id(+) mAbs of either mouse or human origin. We show here that administration of pCDR1 (weekly, i.v., 100 microgram/mouse) in aqueous solution for 5 weeks starting at the time of disease induction with the human 16/6Id prevented the development of clinical manifestations of experimental systemic lupus erythematosus (SLE). Further, 10 weekly injections of pCDR1 to BALB/c mice with an established experimental SLE down-regulated clinical manifestations of SLE (e.g., anti-DNA auto-Abs, leukopenia, proteinuria, immune complex deposits in the kidneys) in the treated mice. Prevention of SLE induction was shown to be associated mainly with a decrease in the levels of IL-2, INFgamma, and the proinflammatory cytokine TNFalpha. On the other hand, the secretion of the immunosuppressive cytokine TGFbeta was elevated. Amelioration of the clinical manifestations of an already established experimental SLE correlated with a dramatic decrease in TNFalpha secretion, elevated levels of TGFbeta, and immunomodulation of the Th1 and Th2 type cytokines to levels close to those observed in healthy mice.

Amino Acid Sequence↗
PubMed2001

Clinical comparison of the measurement of the IOP with the ocular blood flow tonometer, the Tonopen XL and the Goldmann applanation tonometer.

PURPOSE: In addition to measuring ocular blood flow, the ocular blood flow tonometer (OBF) can also be set to solely record intraocular pressure (IOP). In this mode it provides a quick means of tonometry which may allow nursing staff to be more easily trained in its use than conventional Goldmann tonometry. With a view to its eventual use in nurse-led clinics we undertook a study to compare both the OBF tonometer and our currently favoured nurse practitioners tonometer the tonopen XL with Goldmann tonometry. METHOD: IOP was measured in 99 eyes with all three tonometers in a random order. RESULTS: There was not any statistically significant difference between the measurements of all three tonometers. CONCLUSIONS: It is concluded that OBF tonometer can provide clinically useful measurements of intraocular pressure which may in fact be more accurate than the tonopen, however, our opinion is that it possibly is not suitable for a universal glaucoma clinics application.

Adult↗
PubMed2001

An altered peptide ligand inhibits the activities of matrix metalloproteinase-9 and phospholipase C, and inhibits T cell interactions with VCAM-1 induced in vivo by a myasthenogenic T cell epitope.

Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, which are sequences of the human acetylcholine receptor, resulted in MG-associated immune responses. A dual altered peptide ligand (APL) composed of the two APLs of the myasthenogenic peptides inhibited, in vitro and in vivo, those responses. This study was aimed at understanding the mechanism(s) underlying the in vivo inhibitory properties of the dual APL. To this end, we analyzed T cells of mice that were immunized with p259-271 for their adhesiveness toward vascular cell adhesion molecule 1, for the activity of their secreted matrix metalloproteinases (MMPs), and for their intracellular phospholipase C (PLC) activity. Immunization with p259-271 triggered the above three activities and in vivo administration of the dual APL inhibited the latter. Thus, treatment of mice with the dual APL interferes with functions required for T cells to migrate and interact with the self-AChR. This is the first indication that very late antigen 4, MMP-9, and PLC are targets for immunomodulation of autoreactive T cells by altered peptide ligands.

Amino Acid Sequence↗
PubMed2001

Quantification of relative afferent pupillary defects induced by posterior sub-Tenon's, peribulbar, and retrobulbar anaesthetics.

AIMS: The effect of local anaesthetics on optic nerve function can be investigated by quantifying the relative afferent pupillary defect (RAPD). METHODS: The study compared the depth of induced RAPD following posterior sub-Tenon's, retrobulbar, and peribulbar local anaesthetics using crossed polarising filters before cataract surgery (time 1 = 5 minutes), immediately after surgery (time 2 = 42 minutes (av)), and once again on the ward (time 3 = 107 minutes (av)). RESULTS: All patients developed a RAPD. There was no significant difference in the depth of RAPD between the groups at any one time period. The peribulbar group had a significantly steeper decay in RAPD from time 1 to time 2 (p = 0.014). This effect was reduced when the shorter operation time for this group was entered as a cofactor (p = 0.063). By time 3 the RAPDs for all groups had decayed similarly so that no differences could be detected. CONCLUSION: All three anaesthetic methods caused a similar level of disruption to optic nerve conduction immediately following administration and at the time of day case discharge.

Anesthesia, Local↗
PubMed2001

Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxiphylline.

We have previously shown that the clinical manifestations of experimental systemic lupus erythematosus (SLE) correlate with an early increased secretion of TNFalpha and IL-1. In the present study, we examined the efficacy of two therapeutic modalities which lower TNFalpha production or activity, on the clinical manifestations of the disease. Experimental SLE was induced in naive C3H.SW mice by injection of the human anti-DNA monoclonal antibody (mAb) bearing the common idiotype, 16/6 Id. Two weeks after booster injections, treatment with either an anti-TNFalpha mAb, or pentoxiphylline (PTX) was started, for a period of 6 weeks. Production of TNFalpha (by splenocytes) and IL-1 (by peritoneal macrophages) was determined 3 and 7 months after disease induction. The experimental mice were also followed for disease manifestations. Both treatment protocols, with anti-TNFalpha mAb and with PTX, reduced the production of the two pro-inflammatory cytokines. TNFalpha and IL-1, in mice with experimental SLE. Anti-DNA antibodies were significantly lower in the mice treated with either protocol. In addition, a significantly lower rate of leukopenia, proteinuria and immune complex deposition was observed in treated mice. Abrogation of TNFalpha and IL-1 production in the early stages of experimental SLE by an anti-TNFalpha mAb or by PTX improves the clinical status of mice afflicted with this autoimmune disease.

Animals↗
PubMed2000

A peptide based on the CDR3 of an anti-DNA antibody of experimental SLE origin is also a dominant T-cell epitope in (NZBXNZW)F1 lupus-prone mice.

A molecular homology has been demonstrated between sequences of the heavy chain variable regions of the anti-DNA, anti-cardiolipin monoclonal antibody, 2C4C2, isolated from C3H.SW mice with induced systemic lupus erythematosus, and sequences of the anti-DNA monoclonal antibody BW16 originating in the lupus-prone (NZBXNZW)F1 mice. It was of interest to determine whether these homologous sequences function also as immunodominant T-cell epitopes, in order to establish a connection between spontaneous and induced experimental models. Therefore, three peptides were designed and synthesized based on the complementarity determining region (CDR)1, CDR2 and CDR3 of the heavy chain of the monoclonal antibody 2C4C2. In the present study, we compare these peptides with the CDR1- and CDR3-based peptides of another murine anti-DNA antibody; namely, 5G12. The comparison was carried out by analyzing the ability of the peptides to induce T-cell activation in (NZBXNZW)F1 lupus-prone mice and in mouse strains susceptible to induction of experimental systemic lupus erythematosus. Immunization of (NZBXNZW)F1 mice with the 2C4C2 mAb or with its CDR-based peptides, as well as immunization with the 5G12-based CDR peptides, induced significant lymph node proliferation to the pCDR3 of the 5G12 mAb. Naive (NZBXNZW)F1 splenocytes exhibited activation to the same peptide. It is also shown that MHC class II molecules of (NZBXNZW)F1 macrophages bind preferentially the 5G12-based pCDR3. It is proposed that the CDR3-based peptide of 5G12 mAb of experimental lupus is also a dominant and relevant epitope in the (NZBXNZW)F1 lupus-prone mice.

Amino Acid Sequence↗
PubMed2000

Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-regulated, antibody-mediated autoimmune diseases. The major autoantigen in MG is the nicotinic acetylcholine receptor (AChR). Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, were previously shown to be immunodominant T cell epitopes in MG patients as well as, respectively, in SJL and BALB/c mice. A dual analog (termed Lys-262-Ala-207) composed of the tandemly arranged two single amino acid analogs of p195-212 and p259-271 was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual analog could down-regulate myasthenogenic manifestations in mice with EAMG that was induced by inoculation of a pathogenic T cell line. In the present study, the ability of the dual analog to treat EAMG induced in susceptible C57BL/6 mice by native Torpedo AChR was evaluated. Mice that were diagnosed to have clinical symptoms of EAMG were treated with the dual analog by oral administration, 500 microg per mouse three times a week for 5-8 weeks. Treatment with the dual analog down-regulated the clinical manifestations of the ongoing disease as assessed by the clinical score, grip strength (measured by a grip strength meter), and electromyography. The effects on the clinical EAMG correlated with a reduced production of anti-AChR antibody as well as a decrease in the secretion of interleukin-2 and, more dramatically, interferon-gamma, in response to AChR triggering. Thus, the dual analog is an efficient immunomodulator of EAMG in mice and might be of specific therapeutic potential for MG.

Administration, Oral↗
PubMed2000

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

Aging mice of strains susceptible to the induction of experimental systemic lupus erythematosus (SLE) develop a milder disease than young animals. To find out whether the decrease in susceptibility to disease is due to age-associated changes in cytokine profile, we first examined the secretion of cytokines by healthy mice aged 2-15 months. A gradual age-related decline in the levels of interleukin (IL)-2 and interferon (IFN) gamma, and an increase in IL-4, IL-10, IL-1, and tumor necrosis factor (TNF) alpha were observed. Experimental SLE was induced in 2- and 10-month-old mice by immunization with the monoclonal anti-DNA antibody bearing the 16/6 Id. Early increased production of pro-inflammatory cytokines (TNFalpha and IL-1), followed by a peak of the Th1-type cytokines (IL-2, IFNgamma) were observed in young mice. The Th2-type cytokines (IL-4, IL-10) peaked later. In contrast, only a mild increase in all of the above cytokines was determined in 10-month immunized mice. It thus appears that the decline in susceptibility to SLE induction in older mice may be related to changes in the capacity to produce cytokines.

Aging↗
PubMed2000

Immune response of SLE patients to peptides based on the complementarity determining regions of a pathogenic anti-DNA monoclonal antibody.

We have examined the humoral and cellular responses of SLE patients to peptides based on the complementarity-determining regions (CDR) of a monoclonal anti-DNA antibody with a major idiotype- 16/6 Id, in comparison to their responses to the whole 16/6 Id-bearing antibody. Sera of 63% of the SLE patients had antibodies that bound the 16/6 Id, 80% had antibodies to one of the CDR-based peptides, and 40% of the patients reacted with both CDRs. Sera of only a few controls reacted with either the 16/6 Id (6%) or the CDR based peptides (4%) (P < 0.01). Peripheral blood lymphocytes (PBL) of 39% of the patients proliferated in response to the 16/6 Id or to one of the CDR-based peptides (37%), while in the control group the proliferation rates were 66% to the 16/6 Id and 59% to one of the CDR-based peptides (P < 0.05). The correlation between (both) the humoral and cellular immune responses to the CDR-based peptides and to the 16/6 Id suggests the relevance of these peptides to the 16/6 Id and provides additional information on the pathogenic moiety of the latter antibody.

Amino Acid Sequence↗
PubMed2000

Cytokine profile and T cell adhesiveness to endothelial selectins: in vivo induction by a myasthenogenic T cell epitope and immunomodulation by a dual altered peptide ligand.

Myasthenia gravis (MG) is a T cell-regulated antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, that are sequences of the human acetylcholine receptor alpha subunit was shown to induce experimental autoimmune MG (EAMG)-associated immune responses. A peptide composed of the two altered peptide ligands (APL) of the myasthenogenic peptides (designated as dual APL) inhibited, in vitro and in vivo, those responses. The objectives of this study were to examine (i) whether in vivo T cell activation by p259-271 affects the cytokine profile and the T cell migration ability, and (ii) whether the latter are immunomodulated by in vivo administration of the dual APL. Our results showed that immunization of mice with p259-271 enriched the population of lymph node and spleen cells with subsets of T cells with strong adhesiveness towards E- and P-selectins. This enrichment was associated with an acquisition of a T(h)1-type cytokine profile. Treatment of the immunized mice with the dual APL interfered with both the migratory potential of the autoreactive T cells, and the production of the T(h)1-type cytokines IL-2 and IFN-gamma (known to play a pathogenic role in MG and EAMG). T cells derived from APL-treated mice acquired a T(h)3-type cytokine profile, characterized by the secretion of the immunosuppresive cytokine transforming growth factor-ss. Thus, our results suggest that T cell selectin ligands and T cell-derived cytokines are involved in the induction and immunomodulation of EAMG- and MG-associated T cell responses.

Animals↗
PubMed2000

Prospective determination of T-cell responses to S-antigen in Behçet's disease patients and controls.

PURPOSE: To prospectively determine, using two different assays, the lymphocyte proliferative response to a retinal autoantigen (S-antigen) in patients with Behçet's disease who are under treatment for ocular inflammation. METHODS: Patients were evaluated at each visit for signs of ocular inflammation. Peripheral blood leukocytes were harvested and cultured in the presence of bovine S-antigen in a standard culture assay, as well as by limiting dilution using multiple short-term T-cell lines. RESULTS: Five patients were observed for 2 to 10 months. During follow-up, three patients had episodes of ocular inflammation. No consistent change in proliferative response was observed in standard proliferation assays. However, an increase in established T-cell lines was correlated to the presence of ocular inflammation in all three patients. Ocular activity was associated with an increase of 9- to 30-fold in the frequency of short-term T-cell lines. This increase returned to baseline within 1 to 3 months. CONCLUSIONS: An increase in S-antigen-responsive lymphocytes is found in the peripheral blood of patients with Behçet's disease during episodes of ocular inflammation. This increase cannot be measured using standard proliferation assays but requires the use of techniques exploiting the principles of limiting dilution analysis.

Adult↗
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↗