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Biomedical subjects

L Maródi

Publications and source records attributed to L Maródi.

At least 19 recordsLinked to original sources
PubMed2002

No short-term immunological effects of Pneumococcus vaccination in patients with systemic lupus erythematosus.

OBJECTIVE: to investigate the early immunological effects of Pneumococcus vaccination in SLE patients and healthy controls. METHODS: First-four-week follow-up of 18 patients and 9 healthy controls by repeated measurements of anti-nuclear antibodies, anti-dsDNA, C-reactive protein, complement factor 3 (C3) and 4 (C4), total IgG, IgA and IgM. Specific antibody response, percentage of blood lymphocyte populations and whole blood chemiluminescence measurements were carried out in six patients and six controls. RESULTS: No disease flare was detected in the vaccinated patients. all side effects were mild. The concentrations of serum IgG, IgA, C3 and C4 decreased significantly, but still remained within the normal range. The other changes were statistically non-significant. The specific antibody responses to 6B and 23F Pneumococcus serotypes showed striking individual differences. CONCLUSION: There was no short-term immunological effect of Pneumococcus vaccination in the patients with SLE. The non-responders. without any sign of disease activation should possibly be given more immunogenic, new vaccines to avoid life-threatening Pneumococcus infections.

Adult↗
PubMed2002

Deficient interferon-gamma receptor-mediated signaling in neonatal macrophages.

AIM: To describe functional and molecular characteristics of interferon-gamma (IFN-gamma) activation in neonatal mononuclear phagocytes (monocytes and macrophages). METHODS AND RESULTS: Exposure of cord and adult macrophages to IFN-gamma gave quantitatively different results in Candida killing, as well as in release of superoxide anion (O2-). At concentrations of 100 U ml(-1) IFN-gamma, maximal increase in these functions with adult macrophages was achieved, whereas no enhancement of killing and O2- release by cord macrophages could be detected. Expression of IFN-gamma receptors was comparable on cord and adult cells and specific binding of [125I]IFN-gamma to cord monocytes and macrophages was even higher compared with adult cells. By flow cytometry, elements of IFN-gamma receptor-mediated signaling in cord and adult monocytes and macrophages were studied. Monoclonal antibodies against the native form of the signal transducer and activator of transcription-1 (STAT-1) revealed comparable expression of this protein in cord and adult macrophages. However, STAT-1 phosphorylation in response to IFN-gamma was significantly decreased in neonatal monocytes (p < 0.05) and macrophages (p < 0.01) compared with adult cells. CONCLUSION: These data suggest deficient cytokine receptor signaling in neonatal mononuclear phagocytes exposed to IFN-gamma.

Adult↗
PubMed2001

[Disorders of interferon-gamma activation pathways: new group of primary immune deficiency diseases].

Protective immunity to intracellular bacteria such as mycobacteria and salmonella depends on intact cell-mediated immunity. Major effector mechanisms of cell-mediated immunity involve activation of macrophages by T helper-1 cytokines, particularly interferon-gamma. Patients with genetic deficiency of T helper-1 cytokines (IFN-gamma, IL-12) or T helper-1 cytokine receptors (IFN-gamma receptor, IL-12 receptor) are susceptible to infections with poorly pathogenic mycobacteria, and salmonella, suggesting that T helper-1 cytokines are essential in host defense against these pathogens. This review reports on the genetic and clinical characteristics of primary deficiencies of interferon-gamma activation pathways.

Humans↗
PubMed2001

Cytokine receptor signalling in neonatal macrophages: defective STAT-1 phosphorylation in response to stimulation with IFN-gamma.

We reported earlier that neonatal monocyte-derived macrophages (MDM) could not be fully activated with IFN-gamma, a finding that could not be attributed to lower expression of IFN-gamma receptors on the neonatal cells. In this study we explored elements of IFN-gamma R-mediated signalling in cord monocytes and MDM. Intracellular expression of STAT-1 was analysed by flow cytometry. We have assessed phosphorylation of STAT-1 by using MoAbs that distinguish native and phosphorylated forms of STAT-1 on a discrete cell basis. Using MoAbs against the native form of STAT-1 revealed comparable expression of this protein in cord and adult cells (both monocytes and MDM). However, STAT-1 phosphorylation in response to IFN-gamma was significantly decreased in neonatal monocytes (P < 0.05) and MDM (P < 0.01) compared to adult cells (n > 5 for each). These data suggest deficient cytokine-receptor signalling in neonatal mononuclear phagocytes exposed to IFN-gamma. We propose that decreased STAT-1 phosphorylation and activation may represent developmental immaturity and may contribute to the unique susceptibility of neonates to infections by intracellular pathogens.

Adult↗
PubMed2001

A mannose-binding receptor is expressed on human keratinocytes and mediates killing of Candida albicans.

Human keratinocytes are known to kill Candida albicans in vitro, but the mechanism of killing is not yet understood. Here, we demonstrate that spontaneous, ultraviolet-B-light-induced, alpha-melanocyte-stimulating-hormone-induced, and interleukin-8-induced Candida killing by keratinocytes can be inhibited with mannan and mannosylated bovine serum albumin (Man-BSA). A polyclonal goat serum raised against the human macrophage mannose receptor stained suprabasal keratinocytes, but no staining was observed on keratinocytes with a monoclonal antibody (mAb15) specific for the human macrophage mannose receptor. Mannose-affinity chromatography of keratinocyte extract isolated a 200 kDa protein, and on the Western blot the goat antiserum reacted with a 200 kDa protein. In radioligand binding studies, the binding of 125I-Man-BSA to human keratinocytes was inhibited by mannan in a concentration-dependent manner. Analysis of the binding revealed a single class keratinocyte mannose receptor with a KD of 1.4 x 10(-8) M and a Bmax of 1 x 10(4) binding sites per cell. The binding of 125I-Man- BSA to keratinocytes proved to be time-dependent, acid-precipitable, and Ca2+- and trypsin-sensitive. After trypsinization the receptors underwent a rapid recovery at 37 degrees C. These results demonstrate the presence of mannose receptor on human keratinocytes, and its active involvement in the killing of Candida albicans.

Antibodies, Monoclonal↗
PubMed2000

Survival of group B streptococcus type III in mononuclear phagocytes: differential regulation of bacterial killing in cord macrophages by human recombinant gamma interferon and granulocyte-macrophage colony-stimulating factor.

Phagocytic and killing capacities of resident and cytokine-activated human macrophages against group B Streptococcus (GBS) type III were studied. Evidence is presented that monocyte-derived macrophages from cord and adults ingest serum-opsonized GBS but that killing of bacteria was negligible in resident cells. Treatment of adult macrophages with recombinant human gamma interferon (rhIFN-gamma; 100 U/ml) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 200 U/ml) resulted in significant increases of killing of GBS (P < 0.01 for each). The killing capacity of cord macrophages treated with rhGM-CSF was also enhanced compared to that of untreated cells (P < 0.01). However, treatment with rhIFN-gamma resulted in only a moderate increase in the capacity of cord macrophages to kill GBS (P > 0.1). These results mirrored the effect of rhIFN-gamma on candidacidal capacities of cord and adult macrophages, reported earlier from our laboratory. These data indicate differential modulation of neonatal macrophages by rhGM-CSF and rhIFN-gamma. We suggest that administration of rhGM-CSF to neonates with invasive GBS disease may enhance host resistance to these bacteria.

Adult↗
PubMed2000

Activation of human granulocytes by intravenous immunoglobulin preparations is mediated by FcgammaRII and FcgammaRIII receptors.

Previous studies from our laboratory have shown that i.v. Ig (IVIG) exposure triggers superoxide anion (O2) generation by and increases bactericidal capacity of human blood granulocytes. However, the molecular interactions between IVIG and granulocytes have not been evaluated before. The objective of this study was to investigate the role of FcgammaRII and FcgammaRIII receptors in the immunomodulatory effects of IVIG concentrates on granulocytes. We found that four different IVIG preparations (concentration range, 1-10 mg/mL) shared the ability to stimulate O2- release in vitro by granulocytes in a dose-dependent manner. Dimers fractionated from IVIG were significantly more potent in inducing activity of the respiratory burst than were monomers. MAb (concentration range, 0.1-10 microg/mL) specific for FcgammaRII and FcgammaRIII receptors inhibited the IVIG-induced O2- release, with a more profound inhibitory effect observed with anti-FcgammaRIII. These findings suggest the involvement of Fcgamma receptors in triggering O2- release by granulocytes exposed to IVIG. We also report that IVIG added to granulocyte suspensions elicited a rapid and vigorous increase in the concentration of cytosolic free calcium, a finding suggesting direct activation and not priming of granulocytes by IVIG through FcgammaRII and FcgammaRIII receptors. The in vitro effects described here might occur in patients treated with IVIG and may, in part, be responsible for inflammatory reactions evoked by infused Ig concentrates as well as the immunomodulatory effect of Ig in patients with autoimmune and inflammatory diseases.

Antibodies, Monoclonal↗
PubMed1999

Rapid recruitment of late endosomes and lysosomes in mouse macrophages ingesting Candida albicans.

Candida albicans is an important opportunistic pathogen, whose interaction with cells of the immune system, in particular macrophages (MO), is poorly understood. In order to learn more about the nature of the infectious mechanism, internalisation of Candida albicans was studied in mouse MO by confocal immunofluorescence and electron microscopy in comparison with latex beads of similar size, which were coated with mannosyl-lipoarabinomannan (ManLAM) to target the MO mannose receptor (MR). Uptake of Candida yeasts had characteristics of phagocytosis, required intact actin filaments, and depended on the activity of protein kinase C (PKC). Candida phagosomes rapidly attracted lysosome-associated membrane protein (Lamp)-rich vacuoles, indicative of fusion with late endosomes and lysosomes. Rapid recruitment of late endosomes and lysosomes could be observed regardless of heat-inactivation or serum-opsonisation of Candida, but did not follow binding of the mannosylated-beads to MO, which suggest that this phenotype is not MR-specific. The yeasts developed germ tubes within phagolysosomes, distended their membranes and escaped, destroying the non-activated MO. The filamentous form of Candida could penetrate intact MO even when phagocytosis was blocked, and also attracted Lamp-rich organelles. Inhibition of lysosomal acidification and associated lysosomal fusion reduced germ tube formation of Candida within the phagolysosomes. These data suggest that rapid recruitment of late endocytic/lysosomal compartments by internalizing C. albicans favours survival and virulence of this pathogen.

Acids↗
PubMed1998

Characteristics of invasive candidiasis in gamma interferon- and interleukin-4-deficient mice: role of macrophages in host defense against Candida albicans.

Murine models of invasive candidiasis were used to study the in vivo importance of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) in host defense against Candida albicans and to characterize the tissue inflammatory reactions, with special reference to macrophages (Mphi). Knockout (KO) IFN-gamma-deficient (GKO) and IL-4-deficient (IL-4 KO) and C57BL/6 parental mouse strains were challenged intraperitoneally with 10(8) C. albicans blastoconidia. Survival of GKO mice was significantly lower (16.7%) than that of C57BL/6 control (55.5%) and IL-4 KO (61.1%) animals, but was not correlated with the extent of organ colonization. Immunohistological analysis with a panel of myeloid and lymphoid markers revealed multiple renal abscesses, myocarditis, hepatitis, meningoencephalitis, and pneumonia in each strain, with a dominant presence of Mphi. In the absence of IFN-gamma, C. albicans induced striking changes in the phenotype of alveolar Mphi and extensive perivascular lymphoid infiltrates in the lung. Impairment in nitric oxide production by peritoneal Mphi was shown only in GKO mice, and they produced Candida-specific immunoglobulin G (IgG), IgM, IgA, and IgG subclasses in lower titers. Our in vivo studies with KO mice elucidate a critical role for IFN-gamma, but not IL-4, in host defense against C. albicans.

Animals↗
PubMed1998

Augmentation of human macrophage candidacidal capacity by recombinant human myeloperoxidase and granulocyte-macrophage colony-stimulating factor.

Phagocyte myeloperoxidase (MPO) is believed to be particularly important in defense against candida infection. We reported earlier that monocytes, rich in MPO, killed Candida albicans at a significantly higher rate and extent than did monocyte-derived macrophages, known to lack MPO, and that C. albicans is less resistant to MPO-dependent oxidants than less pathogenic Candida species. We hypothesized, therefore, that the capacity of macrophages to kill C. albicans might be improved in the presence of MPO. In this study, we evaluated the ability of recombinant human MPO (rhMPO) to augment the killing of C. albicans by resident macrophages and macrophages activated by recombinant human granulocyte-macrophage colony-stimulating factor. Addition of rhMPO (concentration range, 0.8 to 6.4 U/ml) to suspensions of resident and activated macrophages and opsonized C. albicans resulted in concentration-dependent and significant increases in candida killing. This enhancement was particularly pronounced with activated macrophages, whether C. albicans was opsonized or unopsonized and ingested through the macrophage mannose receptor. rhMPO did not affect the killing of C. albicans by monocytes, nor did it affect phagocytosis of opsonized or unopsonized C. albicans. These results indicate that exogenous rhMPO can augment the candidacidal capacity of both resident and activated macrophages, with a more profound effect on activated cells. We suggest that rhMPO may be effective in the treatment of invasive candidiasis.

Candida albicans↗
PubMed1996

Effect of granulocyte colony-stimulating factor on granulopoiesis of congenital neutropenic children.

We report on two patients with congenital neutropenia, who were treated with filgrastim (recombinant human granulocyte-colony stimulating factor, G-CSF). A poor growth of bone marrow colonies and low sensitivity of colony forming units to colony stimulating factor in vitro before treatment seemed to be associated with a requirement for higher doses of G-CSF to achieve good clinical response in vivo.

Blood Cells↗
PubMed1995

Impaired microbicidal capacity of mononuclear phagocytes from patients with type I Gaucher disease: partial correction by enzyme replacement therapy.

The higher susceptibility to serious bacterial infections in patients with Gaucher disease (GD) may be due in part to defective function of phagocytic cells. We studied five patients with GD (type I) and examined the ability of granulocytes and mononuclear phagocytes from these patients to phagocytose and kill Staphylococcus aureus and to generate superoxide anion (O2-) on stimulation with fully opsonized bacteria. Serum-opsonized staphylococci were ingested equally by phagocytic cells from patients and controls. In the presence of normal serum, the extent of killing of S aureus and the release of O2- by granulocytes over incubation periods of 60 minutes and 30 minutes, respectively, were also equivalent for patients and controls. However, we found that killing of viable bacteria and release of O2- by the patients' monocytes was significantly lower than that in cells from controls (P < .05 for both). The magnitude of differences in killing and O2- release between patients' cells and those from controls was even more profound with monocyte-derived macrophages. Enzyme augmentation with macrophage-targeted glucocerebrosidase preparation for 6 months at doses from 7.5 to 10 U/kg/wk resulted in significant increases of functional activities and O2- generation of monocytes and macrophages along with hematologic and hepatosplenic improvements. These data suggest that mononuclear phagocytes from GD patients are defective in their ability to kill bacteria and to generate reactive oxygen intermediates. Our data also suggest that enzyme substitution may improve functions of monocytes and macrophages in patients with GD that should make them more resistant to severe bacterial infection.

Gaucher Disease↗
PubMed1995

[Successful treatment of cyclic neutropenia associated with hyperimmunoglobulin M syndrome using recombinant granulocyte-colony stimulating factor].

Hyper-IgM syndrome associating with severe neutropenie presenting in irregularis cycles was diagnosed in a 3-year-old male patient. His elder brother died of sepsis which appeared as a consequence of dysgammaglobulinaemia and neutropenia at the age of 9. We could not achieve a parmanent good result with the monthly immunoglobulin substitution and supportive treatment. The candida infection of the gingiva and of the oral mucous membrane expanded to the esophagus resulting in its complete occlusion and temporarily a gastrostomy was needed to feed him. We started with the recombinant human granulocyta colony stimulating factor (rh-G-CSF) treatment at the age of 6. We tried several ways of applying and finally the 10 micrograms/kg/dose given subcutan, for 5-10 days from the nadir of the neutropenic cycle seemed the most effective. The rh-G-CSF treatment resulted in an increase of ANC and the complete resolution of gingivostomatitis. The incidents of infections, the requirement of antibiotics and the duration of hospitalisation were markedly reduced. The consequent improvement in his physical condition made it possible to finally resolve the esophageal stricture surgically. We have not observed any neutropenic cycle since the end of the 14 month rh-G-CSF treatment. Though the medicine was discontinued there has been no recidiva for more than 22 months.

Candidiasis, Oral↗