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Biomedical subjects

P Meroni

Publications and source records attributed to P Meroni.

At least 19 recordsLinked to original sources
PubMed2006

Impact of in utero environment on the offspring of lupus patients.

The number of patients affected by systemic lupus erythematosus (SLE) that decide to have children has greatly increased probably because of recent improvements in the diagnosis and management of the disease. This has stimulated our interest in defining the outcome of children, focusing both on neonatal problems and long term development. SLE patients still carry a risk of pregnancy loss. However, due to careful monitoring and treatment by a multidisciplinary team, the number of losses has dramatically decreased, but an increased number of preterm deliveries is still a problem. Neonatal lupus is linked to the presence of anti-Ro/SS-A and anti-La/SS-B antibodies in the mother, although other factors probably of fetal origin are important. Neonatal lupus is a complex condition whose most serious manifestation is the congenital heart block (CHB). Usually, children with complete CHB need permanent pacing, but apparently do not have neuropsychological problems. Studies focusing on the neuropsychological development of SLE offspring show an increased number of learning disabilities in children with normal intelligence levels. Fetal consequence of maternal treatment need to be considered choosing non teratogenic drugs, but the withdrawal of medications just because the patient is pregnant should be avoided to avoid SLE flares.

Central Nervous System↗
PubMed2001

Prevention and treatment of lethal murine endotoxemia by the novel immunomodulatory agent MFP-14.

Multifunctional protein 14 (MFP-14) is a ubiquitous protein that inhibits the production of tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma), which are involved in the pathogenesis of sepsis. Here, lipopolysaccharide (LPS)-induced lethality in mice was markedly reduced by MFP-14. The treatment also lowered LPS-induced levels of TNF-alpha and IFN-gamma in the blood.

Adjuvants, Immunologic↗
PubMed2001

Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations--a cooperative project of the European Antiphospholipid Forum.

Despite the widely recognized practical importance of anticardiolipin (aCL) ELISA, the reliability of this test has been recently discussed. In order to investigate this area on European scale, we sent to 30 experienced centers a questionnaire focusing on the diagnostic procedures applied to patients with antiphospholipid syndrome (APS) and on the detailed protocols used to perform aCL. Anticardiolipin ELISA was found to be the most frequently performed test in patients with suspected APS, but significant difference was shown among the various protocols. The cross-laboratory multiple examination of ten serum samples evaluated independently by the 24 centers pointed out the difficulty in getting comparable results. Therefore a "consensus" protocol was derived from the aCL methods giving the best performance. The materials and reagents necessary to perform the "consensus" method, including, as putative standards, one IgG and one IgM monoclonal antibody (HCAL and EY2C9) were distributed to 19 Centers. The results of one IgG and one IgM aCL high positive sera measured in serial dilutions were compared. A progressive decrease in the variability of the values obtained for a given sample appeared evident when all the laboratories used the same standard, in their own in-house ELISA and even more in the "consensus" ELISA. Our data show that aCL ELISA standardization is necessary in order to obtain comparable results in different laboratories.

Adult↗
PubMed2000

Dichotomic effects of IFN-gamma on the development of systemic lupus erythematosus-like syndrome in MRL-lpr / lpr mice.

Systemic lupus erythematosus (SLE)-prone female MRL-lpr / lpr (MRL-lpr) mice were treated with mouse or rat IFN-gamma under different experimental conditions, both prophylactically in 6- to 8 week-old animals and therapeutically in 12- to 18-week-old SLE-affected mice. It was found that IFN-gamma heterogeneously modulated the course of the disease in MRL-lpr mice. When administered prophylactically, IFN-gamma favorably modulated the histological, serological and clinical signs of the disease. Relative to untreated or PBS-treated control animals, the MRL-lpr mice which received IFN gamma were virtually free of inflammatory infiltration of the kidneys and the lungs, had lower levels of azotemia with reduction of both circulating IgG1, IgG2a and IgG3 and anti-double strand (ds) and single strand (ss) DNA antibodies, milder skin vasculitis, significantly reduced enlargement of their lymph nodes and lower weight of the spleens. IFN-gamma also lowered the rate of mortality of MRL-lpr mice. In contrast to these findings, therapeutically administered IFN-gamma worsened the course of the disease in MRL-lpr mice, which exhibited increased proteinuria, higher levels of IgG2a and IgG3 and anti-ds and -ss DNA antibodies, more aggressive nephritis and died at an earlier age than PBS-treated control mice. The dichotomic effect of IFN-gamma on disease manifestation in MRL-lpr mice offers new insights into the complex role of this cytokine in the regulation of systemic autoimmunity such as SLE.

Animals↗
PubMed2000

Essential pathogenetic role for interferon (IFN-)gamma in concanavalin A-induced T cell-dependent hepatitis: exacerbation by exogenous IFN-gamma and prevention by IFN-gamma receptor-immunoglobulin fusion protein.

We have studied the effects of either exogenously-administered interferon (IFN-)gamma or of a nonimmunogenic mouse IFN-gamma receptor-Immunoglobulin (IFN-gamma R-Ig) fusion protein on the development of Concanavalin (Con)A-induced hepatitis in NMRI mice. PBS-treated control mice injected with 20 mg/kg ConA developed classical serological and histological signs of hepatitis with elevation of transaminases in the blood and infiltration of the liver by mononuclear cells and neutrophils. Treating the mice with rat IFN-gamma 24 h prior to and 1 h after ConA-challenge markedly exacerbated these signs of hepatitis in a dose-dependent fashion. Moreover, mice injected with lower, non hepatitogenic, doses of ConA (10, 5 mg/kg) became fully susceptible to develop hepatitis upon similar treatment with IFN-gamma. Concordantly, ConA-induced hepatitis was abrogated by either IFN-gamma R-Ig fusion protein or anti-IFN-gamma mAb. These data provide further evidence for the central pathogenetic role of endogenous IFN-gamma in ConA-induced hepatitis and demonstrate the feasibility to prevent disease development by means of a non immunogenic IFN-gamma R-Ig fusion protein.

Animals↗
PubMed2000

Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-gamma-dependent mechanism.

Concanavalin A (ConA)-induced hepatitis is a cell-mediated immunoinflammatory condition similar to human autoimmune hepatitis. We investigated the role of interleukin 12 (IL-12) in hepatitis induced in NMRI and C57/BL6 mice by a single injection of ConA. Recombinant murine IL-12 administered 24 hours and 1 hour prior to ConA exacerbated both transaminase activities in plasma and histologic signs of hepatitis. These markers of liver injury were significantly reduced by prophylactic, but not therapeutic treatment with anti-IL-12 monoclonal antibody (mAb). The disease-modulatory effects of IL-12 and anti-IL-12 mAb were associated with profound and reverse modifications of a ConA-induced increase in the circulating levels of IL-4, IL-6, interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). Relative to control animals receiving ConA alone, the plasma levels of these cytokines were all augmented in IL-12/ConA-treated mice and diminished in anti-IL-12 mAb/ConA-treated mice. Anti-IFN-gamma mAb also impeded the appearance of IL-12/ConA-induced hepatitis. Thus, IL-12-induced production of IFN-gamma might play a role in mediating the hepatitis-inducing effect of ConA. However, IL-12p40-deficient C57/BL6 mice were as susceptible as wild-type controls to the hepatitis-inducing effect of ConA.

Animals↗
PubMed2000

The antiinflammatory cytokine interleukin-13 is not detectable in the circulation of multiple sclerosis patients and is not inducible by interferon-beta1b treatment, that neither modifies its ex vivo secretion from peripheral blood mononuclear cells.

Interleukin (IL)-13 is a T-cell derived cytokine closely related to IL-4 that possesses powerful antiinflammatory properties. In this study we have evaluated the blood levels of IL-13 in patients with multiple sclerosis (MS), either with relapsing remitting or secondary chronic progressive (CP) course of the disease, and have also examined the effect of treatment with interferon (IFN)-beta 1b given on alternate days for 10 days both on the serum levels of IL-13 and on the ex vivo secretory capacity of mononuclear cells from MS patients. IL-13 was not detectable in the circulation of MS patients regardless of whether RR MS patients with stable or active disease or those suffering from secondary CP MS were studied. Moreover, circulating levels of IL-13 were not induced by treatment with IFN- beta1b, that was neither capable of modifying the ex vivo IL-13 secretory capacity of peripheral blood mononuclear cells. These data neither anticipate a role for endogenous IL-13 in down-regulating immunoinflammation during MS attacks nor suggest that IFN-betalb treatment exerts its favourable effects on the course of RR MS by augmenting the secretion of this antiinflammatory cytokine.

Adult↗
PubMed1999

Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency.

One single intra-venous (i.v.) injection of Concanavalin A (Con A) into mice provokes a cell-mediated immunoinflammatory hepatitis. We have presently evaluated the immunopharmacological effects of exogenous interleukin (IL)-10 and the role of endogenous IL-10 in this model by using exogenous IL-10, anti-IL-10 monoclonal antibody (mAb) and mice with disrupted IL-10 gene (IL-10 KO mice). Whilst exogenous IL-10 administered in a prophylactic (1 h prior to Con A) and even "early" therapeutic fashion (30 min after Con A) reduced the elevation of transaminase activities in plasma in a dose-dependent manner, observed in control mice, these biochemical markers of liver injury were significantly increased both in IL-10 KO mice as well as in those receiving anti-IL-10 mAb. Interestingly, doses of Con A lower than 20 mg/kg that were only capable of inducing slight serological signs of hepatitis in mice, exerted marked hepatitic effects when administered to either anti-IL-10 mAb-treated mice or to IL-10 KO mice. The disease modulating effects of exogenous IL-10 and either genetical or pharmacologically-induced IL-10 deficiency were associated with profound and opposite modifications of the Con A-induced increase in the circulating levels of IFN-gamma and TNF-alpha. Relative to control animals, the blood levels of these cytokines were diminished in IL-10-treated mice and augmented in both IL-10 KO mice and anti-IL-10 mAb-treated mice. These results prove the physiological antiinflammatory role of endogenous IL-10 in Con A induced hepatitis and the beneficial effects of IL-10 treatment to prevent this condition.

Alanine Transaminase↗
PubMed1998

Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome.

BACKGROUND: The antiphospholipid syndrome (APS) entails a prothrombotic state associated with the presence of anticardiolipin antibodies (aCL). aCL were shown to promote endothelial cell and platelet activation and to induce an APS-like syndrome in mice when administered intravenously. Recent data suggest that aCL target the plasma cofactor beta2-glycoprotein I (beta2GPI) rather than negatively charged phospholipids. However, it has not been determined whether different epitope-specific anti-beta2GPI antibodies obtained from one patient possess pathogenic properties. METHODS AND RESULTS: Three beta2GPI-binding IgM monoclonal antibodies (mAbs) (ILA-1, ILA-3, and ILA-4) were cloned from a patient with APS. The three antibodies were shown to bind beta2GPI immobilized on irradiated plates, yet only ILA-1 bound beta2GPI coated onto nonirradiated plates. Furthermore, when using the anti-beta2GPI enzyme-linked immunosorbent assay, ILA-1 was the only mAb inhibited by fluid phase beta2GPI. ILA-1 and ILA-3, but not ILA-4, induced adherence of U937 cells to endothelial cells in vitro (reflecting activation of endothelial cells). mAbs ILA-1 and ILA-3 as opposed to ILA-4 induced significant expression of adhesion molecules when preincubated with human umbilical vein endothelial cells. Passive administration of ILA-1 and ILA-3 to pregnant BALB/c mice induced clinical findings consistent with APS (increased fetal resorptions, reduced platelet counts, and prolonged activated partial thromboplastin time), whereas both ILA-4 and the control human IgM did not produce similar effects. CONCLUSIONS: The results of the study demonstrate the differential effects of various populations of anti-beta2GPI antibodies on endothelial cell activation and on experimental APS.

Adult↗
PubMed1998

Deoxyspergualin neither counteracts lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin-B (SEB) induced lethality in mice nor does it modulate the release of tumor necrosis factor-alpha.

To gain further insights into the immunopharmacological mode of action of the immunosuppressant antibiotic deoxyspergualin (DSP), its effects were evaluated in murine lethal endo- and exotoxemia. These are two cytokine-mediated macrophage and T cell dependent immunoinflammatory conditions that can be induced in D-Galactosamine (D-Gal) presensitized mice by the injections with either LPS or SEB, respectively. The results show that prophylactic treatment with DSP (2.5 or 5 mg/kg bd.wt. 48, 24 and 2 h prior to challenge) neither improved the rate of survival, nor influenced the massive increase in the blood levels of tumor necrosis factor-alpha which followed the challenge with LPS or SEB. In sharp contrast, these clinical and seroimmunological events were both markedly counteracted by prophylactic treatment with sodium fusidate, another immunosuppressive agent used as control.

Animals↗
PubMed1998

Sodium fusidate in Gillain-Barré syndrome: a case report.

A patient with Guillain-Barré syndrome is reported on who responded favourably to a short course treatment with the novel immunosuppressant sodium fusidate (Fucidin), given at a daily dose of 1.5 g for one week. Along with prompt and clear cut clinical improvement, treatment with Fucidin was associated with a rapid decline in the blood concentrations of inflammatory cytokines presumably implicated in the pathogenesis of Guillain-Barré syndrome such as interleukin-2, interferon-gamma, and tumor necrosis factor-alpha. The ex vivo production of these cytokines was also markedly diminished compared with pretreatment values. Fucidin was well tolerated and no clinical or biochemical side effects were seen.

Dose-Response Relationship, Drug↗
PubMed1998

Anti beta2-glycoprotein I antibodies: clinical significance.

The introduction of anticardiolipin antibody (aCL) assay, described in 1983, was able to focus much attention on the study of patients suffering from thrombosis, repeated fetal loss and thrombocytopenia, and allowing the identification of the so called antiphospholipid syndrome (APS). The identification of beta2 glycoprotein I (beta2GPI) as an essential component of the antigenic complex recognized by aCL suggested that this molecule could be a direct target of the antibody response. Since then, different groups have described ELISAs for the detection of anti beta2GPI antibodies, applied to the clinical evaluation of patients with APS, and showing an overall better specificity. Recently, anti beta2GPI were also shown to bind apoptotic bodies resulting in an alteration of their physiological clearance with the triggering of TNFalpha release. This observation suggests that anti beta2GPI may also modify the immunogenicity of apoptotic bodies and of the autoantigens that they contain.

Antibodies, Anticardiolipin↗
PubMed1997

Prevention of spontaneous autoimmune diabetes in diabetes-prone BB rats by prophylactic treatment with antirat interferon-gamma antibody.

The role of endogenous interferon-gamma (IFN gamma) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BB rats was evaluated. Several groups of these animals were treated under different, experimental conditions with a purified polyclonal antibody (Ab), antirat IFN gamma. The results show that when administered at doses of 100 or 200 micrograms/week from the 30/33th until the 105th day of age, the anti-IFN gamma Ab reversibly reduced the incidence of IDDM compared to that in control rats treated with either irrelevant rabbit IgG or PBS. Moreover, when given up to the 105th day of age, these doses of anti-IFN gamma Abs exerted comparable preventive effects regardless of whether application started as early as within 24 h after birth or at the end of the prediabetic period (e.g. 70/75 days). In contrast, under none of the above experimental conditions did larger doses of anti-IFN gamma Ab (500 micrograms or 1 mg/week) exert antidiabetogenic effects in the BB rats. Apparently, this was due to the exuberant production of neutralizing Abs elicited by the large amount of the xenogeneic Ab injected. At histoimmunological analyses, the BB rats treated with 200 micrograms/ week anti-IFN gamma Abs from 30-80 days of age exhibited a milder insulitic process along with diminished spleen frequency of activated lymphoid cells (MHC class II and interleukin-2 receptor positive). Taken together, these results provide further in vivo evidence for the central pathogenic role of IFN gamma in BB rat IDDM and anticipate the usefulness of specific IFN gamma inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic forms of specific IFN gamma inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFN gamma-oriented approaches.

Animals↗
PubMed1996

The anti-beta2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native beta2-glycoprotein I and preserved during species' evolution.

To characterize the reactivity pattern of Abs directed to beta2-glycoprotein I (anti-beta2GPI) in patients with anti-phospholipid syndrome, we have purified anti-beta2GPI Abs by affinity chromatography using the IgG fractions from sera of five different anti-phospholipid syndrome patients. Affinity-purified anti-beta2GPI were shown to be representative of Abs found in human sera because their activity could be virtually abolished from the IgG preparations after repeated absorptions on immobilized human beta2GPI column. Our results show that affinity-purified anti-beta2GPI: 1) do react with beta2GPI in the absence of any phospholipid, as demonstrated by the lack of phosphorus contaminant in the employed reagents, as well as by their comparable binding activity before and after extensive delipidation procedure; 2) can recognize beta2GPI regardless of its origin from different animal species; 3) are able to bind soluble beta2GPI with a mean Kd value of 4.65 x 10(-6) M (range 3, 4-7, 2 x 10(-6) M); 4) significantly enhance their binding avidity when beta2GPI is linked to a solid support; and 5) appear to be mainly monoreactive autoantibodies. In conclusion, we have shown that human polyclonal anti-beta2GPI are low affinity, mainly monoreactive autoantibodies directed to an epitope located on native beta2GPI, preserved along the species evolution.

Adolescent↗