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Biomedical subjects

A Tarkowski

Publications and source records attributed to A Tarkowski.

At least 73 records · Page 4Linked to original sources
PubMed1999

The effect of site-specific monoclonal antibodies directed to toxic shock syndrome toxin-1 in experimental Staphylococcus aureus arthritis.

Staphylococcus aureus produces a large number of potential virulence factors, among these the superantigen toxic shock syndrome toxin-1 (TSST-1). We have recently demonstrated that TSST-1 is involved in the pathogenesis of septic arthritis. Recent data show that the TSST-1 molecule is composed of two distinct domains, one proposed to interact with T cell receptor (TCR) and one with the MHC class II. The aim of this study was to assess if interaction between TSST-1-specific MoAbs directed to sites on the MHC and/or TCR Vbeta affects the development of experimental S. aureus-induced arthritis. For that purpose we used a panel of seven MoAbs, which were injected intraperitoneally before and after inoculation with a TSST-1-producing S. aureus strain. Administration of antibodies did not affect the development of arthritis, suggesting inefficacy of such a procedure in neutralization of exotoxin-mediated disease manifestations.

Animals↗
PubMed1999

Interaction with complement receptor 1 (CD35) leads to amelioration of sepsis-triggered mortality but aggravation of arthritis during Staphylococcus aureus infection.

The aim of this study was to assess the importance of complement receptor 1 (CR1, CD35) in Staphylococcus aureus arthritis and sepsis. The murine model of haematogenously acquired septic arthritis was used, injecting toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus LS-1 intravenously. CR1 was blocked using immunoglobulin G (IgG) rat antimouse CR1 monoclonal antibody (MoAb) (8C12). Evaluation of arthritis was performed clinically and histopathologically. In addition, the effect of blocking CR1 was assessed on the phagocytic activity of leucocytes and on T-cell dependent and independent inflammation. Seven days after inoculation with bacteria, 96% of CR1 MoAb-treated mice had clinical symptoms of arthritis compared with 58% of the control animals (P < 0.01). The severity of arthritis, expressed as mean arthritic index, was 2.9 +/- 0.5 and 1.4 +/- 0.5, respectively (P = 0.004). Fifteen days after bacterial inoculation, all CR1 MoAb-treated mice had severe arthritis (mean arthritic index 6.3 +/- 0.6), while only 77% of controls were affected (mean arthritic index 2.9 +/- 0.6; P = 0.002). The potential explanation of these findings is that treatment with CR1 MoAb significantly increases the polymorphonuclear cell-dependent inflammatory response as a result of enhanced vasodilatation in treated animals. We conclude that treatment with CR1 MoAb leads to amelioration of sepsis-induced mortality during S. aureus infection, possibly as a result of the increased phagocytic activity of peripheral phagocytes.

Animals↗
PubMed1999

Participation of CD1 molecules in the presentation of bacterial protein antigens in humans.

Human CD1 molecules, expressed on the surface of professional antigen-presenting cells (including dendritic cells, Langerhans' cells, B cells and activated monocytes) are structurally homologous to major histocompatibility complex (MHC) class I and class II molecules. CD1b and CD1c have been shown to present nonpeptide bacterial antigens to T cells. We hypothesized that CD1 molecules may also be involved in the presentation of bacterial protein antigens. Human peripheral blood mononuclear cells (PBMC) were exposed to two medically important proteins, tetanus toxoid (TT) and purified protein derivative (PPD), with and without murine monoclonal antibodies (MoAbs) specific for CD1a, CD1b and CD1c. All the MoAbs substantially inhibited the proliferative responses of PBMC to TT and PPD. Simultaneous interaction of CD1 and MHC class II molecules was even more inhibitory to these antigen-specific proliferative responses. In contrast, neither mixed lymphocyte reaction nor superantigen and mitogenic responses were affected by CD1-specific antibodies, indicating a certain restriction pattern in antigen presentation. Our findings suggest that, besides MHC class I and II molecules, there is a family of nonpolymorphic cell surface molecules that is able to present certain bacterial protein antigens to T cells.

Antibodies, Monoclonal↗
PubMed1999

Protection against Staphylococcus aureus sepsis by vaccination with recombinant staphylococcal enterotoxin A devoid of superantigenicity.

Staphylococcal exotoxins are virulence determinants in Staphylococcus aureus arthritis and septicemia. To assess the utility of enterotoxins as vaccine candidates for these diseases, a genetically modified staphylococcal enterotoxin A (SEA) that lacks superantigenic properties was used. Mice immunized with recombinant (r) SEA had significantly longer survival than control immunized mice and lost significantly less weight than the controls. Transfer of SEA-specific antibodies to naive mice resulted in good protection against death in staphylococcal sepsis. In vitro proliferative responses to SEA by naive lymphocytes were almost totally abolished on incubation with serum from rSEA but not with control antigen-immunized mice. These results suggest that immunization with rSEA devoid of superantigenic properties provides good protection against S. aureus sepsis. In addition, the data indicate that the protection is at least in part mediated by SEA neutralizing antibodies.

Animals↗
PubMed1999

Staphylococcus aureus-induced inflammation and bone destruction in experimental models of septic arthritis.

Staphylococcus aureus is the most common cause of septic arthritis. This disease often leads to severe joint destruction and high mortality. An experimental model of S. aureus arthritis has been developed to study the course of inflammation and joint destruction, to elucidate the role of bacterial and host factors for joint pathology and mortality, and to develop therapeutical and preventive devices against septic arthritis and sepsis. Results show that the innate immune system is crucial in defending the host against staphylococcal infection while components of the specific immune system, T and B lymphocytes and their products, are detrimental to the host, mediating joint destruction and increasing mortality rates. Staphylococcal capsule polysaccharides, toxins, cell wall-attached adhesins and possibly also the chromosomal DNA are virulence determinants in S. aureus arthritis. Several vaccine candidates have recently been described which protects against staphylococcal infections, e.g. staphylococcal surface polysaccharides, enterotoxins devoid of their superantigenic properties and collagen adhesin. There are also new approaches suggested for treatment of ongoing infections, such as the combined use of antibiotics and corticosteroids.

Adhesins, Bacterial↗
PubMed1999

Alpha-toxin and gamma-toxin jointly promote Staphylococcus aureus virulence in murine septic arthritis.

Septic arthritis is a common and feared complication of staphylococcal infections. Staphylococcus aureus produces a number of potential virulence factors including certain adhesins and enterotoxins. In this study we have assessed the roles of cytolytic toxins in the development of septic arthritis by inoculating mice with S. aureus wild-type strain 8325-4 or isogenic mutants differing in the expression of alpha-, beta-, and gamma-toxin production patterns. Mice inoculated with either an alpha- or beta-toxin mutant showed degrees of inflammation, joint damage, and weight decrease similar to wild-type-inoculated mice. In contrast, mice inoculated with either double (alpha- and gamma-toxin-deficient)- or triple (alpha-, beta-, and gamma-toxin-deficient)-mutant S. aureus strains showed lower frequency and severity of arthritis, measured both clinically and histologically, than mice inoculated with the wild-type strain. We conclude that simultaneous production of alpha- and gamma-toxin is a virulence factor in S. aureus arthritis.

Animals↗
PubMed1999

Intrathecal expression of proteins regulating apoptosis in acute stroke.

BACKGROUND AND PURPOSE: The neuronal death that accompanies an ischemic stroke has previously been attributed to a necrotic process. However, numerous studies in experimental models of ischemia have recently indicated that programmed cell death, also called apoptosis, may contribute to neuronal death. The aim of the present study was to investigate the intrathecal levels of proteins regulating apoptosis in acute stroke and to relate these levels to brain damage and to production of proinflammatory and anti-inflammatory cytokines. METHODS: Thirty stroke patients were studied prospectively on days 0 to 4, 7 to 9, 21 to 26, and after day 90 with clinical evaluation, radiological assessment, and analysis of cerebrospinal fluid (CSF) levels of soluble (s) Fas/APO-1 and sbcl-2, 2 proteins that regulate apoptosis. In addition, analysis of the intrathecal levels of cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha was performed. Nineteen CSF samples from healthy subjects were used for control purposes. The patients were examined with MRI 1 to 3 months after stroke onset for measurement of infarct volume RESULTS: Significantly decreased CSF levels of sFas/APO-1 were observed during the entire observation period, with a maximal decrease on day 21 after the onset of stroke. The intrathecal levels of sFas/APO-1 were significantly negatively correlated with the volume of brain infarct and with the neurological deficit 3 weeks and 3 months after the onset of the stroke. In addition, the intrathecal levels of sFas/APO-1 were significantly correlated with the levels of IL-1beta, IL-6, IL-10, and GM-CSF 3 weeks after the onset of the disease. The intrathecal levels of sbcl-2 were significantly decreased during the first 3 days after stroke onset and at the same time were positively correlated with the levels of IL-6 and tumor necrosis factor-alpha. CONCLUSIONS: Our study demonstrates decreased intrathecal levels of proteins with antiapoptotic properties, suggesting that patients with acute stroke display a propensity toward apoptosis. Control of factors regulating apoptosis may lead to decreased delayed brain damage in stroke.

Acute Disease↗
PubMed1999

Oral microbial flora in Sjögren's syndrome.

OBJECTIVE: To study presence of microorganisms associated with caries, gingivitis, oral opportunistic infections, and extent of hyposalivation in dentate patients with primary and secondary Sjögren's syndrome (SS). METHODS: An oral clinical examination was performed. The salivary flow was measured and a rinsing sample analyzed for presence of specific microorganisms. The results were compared to those of healthy controls matched for sex, age, and number of teeth. RESULTS: In patients with undetectable salivary flow at rest, mean number and proportion of mutans streptococci and lactobacilli showed a tendency to be increased, as well as the frequency of Candida. They also displayed an increased proportion of filled surfaces. In contrast, gingivitis and the numbers of microorganisms associated with gingivitis were comparable to those found in the healthy controls. CONCLUSION: Patients with SS and severe hyposalivation harbor oral flora associated with the development of caries and frequent presence of retention sites, indicating a need for efficient preventive dental care.

Adult↗
PubMed1998

TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus.

To evaluate the importance of the proinflammatory cytokines TNF and lymphotoxin-alpha (LT alpha) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LT alpha-double-deficient mice raised on the C57BL/6 background. Mice were i.v. inoculated with a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus strain, LS-1. Intravenous inoculation of a high dose of bacteria (1 x 10(7)/mouse) resulted in 67% mortality in TNF/LT alpha-deficient mice, whereas none of the controls died (p = 0.009). Those results correlated to a significantly decreased phagocytosis in vitro and inefficient bacterial clearance in vivo in mice lacking capacity to produce TNF/LT alpha. Thus, at day 6 after inoculation, S. aureus could not be found in the bloodstream of controls, but bacteremia developed in all TNF/LT alpha-deficient mice examined (p = 0.02). Interestingly, upon infection with a lower dose of staphylococci (3 x 10(6)/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-type group as compared with the TNF/LT alpha-deficient mice (40% vs 13%). Histopathologic examination revealed a lower frequency of synovitis (38% vs 90%, p < 0.05) and erosivity (25% vs 60%, NS) in TNF/LT alpha-deficient mice as compared with wild-type counterparts. Our results show the importance of TNF/LT alpha in defense against systemic S. aureus infections and point out the detrimental role of these cytokines as mediators of inflammatory response in S. aureus arthritis.

Animals↗
PubMed1998

Vaccination with a recombinant fragment of collagen adhesin provides protection against Staphylococcus aureus-mediated septic death.

Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. Morbidity and mortality due to infections such as sepsis, osteomyelitis, septic arthritis, and invasive endocarditis remain high despite the use of antibiotics. The emergence of antibiotic resistant super bugs mandates that alternative strategies for the prevention and treatment of S. aureus infections are developed. We investigated the ability of vaccination with a recombinant fragment of the S. aureus collagen adhesin to protect mice against sepsis-induced death. Actively immunized NMRI mice were intravenously inoculated with the S. aureus clinical isolate strain Phillips. 14 d after inoculation, mortality in the collagen adhesin-vaccinated group was only 13%, compared with 87% in the control antigen immunized group (P < 0.001). To determine if the protective effect was antibody mediated, we passively immunized naive mice with collagen adhesin-specific antibodies. Similar to the active immunization strategy, passive transfer of collagen adhesin-specific antibodies protected mice against sepsis-induced death. In vitro experiments indicated that S. aureus opsonized with sera from collagen adhesin immunized mice promoted phagocytic uptake and enhanced intracellular killing compared with bacteria opsonized with sera from control animals. These results indicate that the collagen adhesin is a viable target in the development of immunotherapeutics against S. aureus.

Adhesins, Bacterial↗
PubMed1998

Staphylococcus aureus-induced septic arthritis and septic death is decreased in IL-4-deficient mice: role of IL-4 as promoter for bacterial growth.

Lack of IL-4 has been shown to be protective in some experimental models of infectious diseases in mice such as cutaneous leishmaniasis. At the same time IL-4, together with other Th2 cytokines, including IL-10 and IL-13, is known as an anti-inflammatory cytokine with the potential to down-regulate proinflammatory cytokine production. To investigate the role of IL-4 in experimental Staphylococcus aureus-induced and T lymphocyte-mediated arthritis, IL-4-deficient C57BL/6 mice (IL-4(-/-)) and their congenic controls (IL-4(+/+)) were inoculated with a toxic shock syndrome toxin-1-producing S. aureus strain. In IL-4(+/+) mice, arthritis peaked 14 days after bacterial inoculation, whereas, at that time, IL-4(-/-) mice displayed significantly less frequent (p < 0.05) joint inflammation. Paralleling lower frequency of arthritis, IL-4-deficient mice showed a decreased bacterial burden in joints (p = 0.014) and kidneys (p = 0.029), as well as lower infection-triggered weight decrease and mortality. In vitro, IL-4 inhibited intracellular killing of S. aureus in infected macrophages, without affecting phagocytosis. This finding may explain the enhanced staphylococcal clearance observed in IL-4(-/-) mice in vivo. Our results suggest that IL-4 and IL-4-dependent Th2 responses promote septic arthritis and sepsis-related mortality by inhibition of bacterial clearance during S. aureus infection.

Animals↗
PubMed1998

Arthritis and sepsis caused by Staphylococcus aureus: can the tissue injury be reduced by modulating the host's immune system?

In recent years, a number of virulence factors that are either expressed, secreted or sequestered by staphylococci have been shown to affect the outcome of the infective process. Secretion of superantigens and exposure of the immune system to sequestered bacterial DNA aggravates the inflammatory response of the infected host to a point that can be life threatening. This exaggerated inflammatory response is mediated by cytokines originating from activated T cells and macrophages. Recent studies show that downregulation of lymphocyte and macrophage responses (e.g. by treatment with corticosteroids) significantly alleviates the outcome of staphylococcal infections when combined with appropriate antibiotics.

Animals↗
PubMed1998

The dual role of interferon-gamma in experimental Staphylococcus aureus septicaemia versus arthritis.

To evaluate the role of interferon-gamma (IFN-gamma) in Staphylococcus aureus infection, we investigated the effects of supplementation with and neutralization of IFN-gamma during septicaemia and arthritis in a murine model. In vivo administration of IFN-gamma both before and after bacterial inoculation significantly decreased mortality on one hand but enhanced the development of arthritis on the other. Treatment of mice with anti-IFN-gamma monoclonal antibodies (mAb) before and after bacterial inoculation did not significantly influence the survival rate but decreased the frequency and severity of arthritis. The beneficial effect of supplementation with IFN-gamma on septicaemia was correlated to the increased phagocytosis and bacterial clearance from liver and kidneys. The down-regulation of the development of arthritis by anti-IFN-gamma mAb was accompanied by the decreased serum tumour necrosis factor-alpha, interleukin-6 and interleukin-1 beta levels. These results demonstrate a significant role for IFN-gamma in simultaneous protection against septicaemia but promotion for the development of septic arthritis.

Animals↗
PubMed1998

V beta 11+ T-lymphocyte expansion by toxic shock syndrome toxin-1 differs in mice bearing H-2q versus H-2b haplotypes.

We have recently demonstrated that toxic shock syndrome toxin-1 (TSST-1) expanded V beta 11+ T lymphocytes contribute to Staphylococcus aureus arthritis and sepsis-induced mortality. Interestingly, V beta 11+ T-cell mediated joint pathology varies in different mouse strains. In this study, we characterized the in vitro pattern of V beta 11+ T-cell expansion by TSST-1 in mice with various genetic backgrounds. Mice expressing major histocompatibility complex (MHC) class II I-E molecules did not expand V beta 11+ T cells upon stimulation with TSST-1. Using B10 congeneic I-E negative mouse strains, we found that the TSST-1-expanded V beta 11+ T cells in B10Q (H-2q) and B10M (H-2f) mice but not in B10B (H-2b) mice. Antigen-presenting cells (APC) from B10Q mice, L cells and lymphoma cell line transfected with a q gene did not restore the deficient V beta 11+ T-cell expansion by TSST-1 in purified T cells from B10B mice. In contrast, I-Ab APC were able to stimulate V beta 11+ T cells from H-2q mice. Furthermore, V beta 11+ T cells in H-2b mice did expand when exposed to staphylococcal enterotoxin A (SEA). These findings suggest that the T-cell repertoire, skewed by clonal deletion and inactivation of self-reactive T cells, accounts for the different magnitude of V beta 11+ T-cell expansion among the different mouse strains.

Animals↗
PubMed1998

Localization of the brain lesion affects the lateralization of T-lymphocyte dependent cutaneous inflammation. Evidence for an immunoregulatory role of the right frontal cortex-putamen region.

We have previously demonstrated that brain lesions caused by stroke led to the lateralization of T-cell dependent inflammation. The purpose of this study was to assess the impact of localization of the brain lesion on lateralization of immune responsiveness. The delayed-type hypersensitivity (DTH) reaction was used as an in vivo measure of antigen specific T-lymphocyte reactivity. All stroke patients were examined with computed scan tomography (CT) of the brain to ascertain the localization and extent of the brain lesion. Patients with right-sided brain lesions displayed significantly larger (P = 0.008) DTH responses on the paretic side compared to the contralateral side. Detailed analysis of the localization of the brain lesion revealed that infarcts encompassing frontal lobe-putamen led to significantly larger (P = 0.007) DTH responses on the paretic side compared to the contralateral side. Localization of the brain lesion affects the lateralization of DTH, supporting an asymmetrical modulation of the immune response. In addition, our study points to the frontal cortex-putamen as a putative brain centre regulating the magnitude of immune responses.

Adult↗
PubMed1998

Expression of the mucosal lymphocyte integrin alphaEbeta7 and its ligand E-cadherin in salivary glands of patients with Sjögren's syndrome.

The expression of the mucosal lymphocyte integrin alphaEbeta7 and its ligand E-cadherin was analyzed in sialadenitic lesions of patients with Sjögren's syndrome in order to assess the potential interactions between the mucosal and the systemic immunological compartments. Immunohistochemical evaluation of the inflammatory infiltrates in the salivary gland tissues in Sjögren's syndrome patients revealed presence of alphaEbeta7-integrin-expressing lymphocytes, in 18 of 20 biopsies examined. The ligand for alphaEbeta7, E-cadherin was also found in 18 of 20 salivary gland biopsies analysed. These results suggest homing of lymphocytes derived from the gut epithelium through the blood stream to inflamed salivary gland tissue followed by in situ interaction with E-cadherin expressing cells, the ligand for alphaEbeta7 expressing T lymphocytes.

Cadherins↗
PubMed1998

Local and systemic TCR V gene expression in advanced periodontal disease.

The aim of the present investigation was to study the expression of specific alpha/beta T cell receptor (TCR) gene products in relation to some microbiological and immunological features of advanced destructive periodontitis. 21 individuals with advanced periodontal disease (diseased group) and 16 age- and sex-matched healthy subjects (healthy group) were recruited. Following a clinical examination of the diseased group, the 3 deepest interproximal sites in the upper and lower premolar- or molar segments (i.e., 12 sites in each individual) were selected for further analysis. Samples from the subgingival microbiota were obtained from the pocket of the selected sites and were prepared for a microbiological examination. The gingival tissue at one of the selected sites was also biopsied. Each excised soft tissue specimen was divided into 2 equal portions. One portion of the biopsy was prepared for histometric and morphometric analyses. The 2nd portion was snap frozen and prepared for immunohistochemical analysis. A sample of peripheral blood was obtained from each individual of the diseased and the healthy group and prepared for immunohistochemical analysis. The selected sites of the diseased group harbored varying numbers of microorganisms which have been associated with periodontal disease. The excised gingival tissue contained inflammatory lesions with substantial numbers of lymphocytes and plasma cells including T- and B-cells and a TCR V alpha/beta gene repertoire dominated by Vbeta 17. The TCR profile of the lesion, however, differed markedly from that of the circulating blood of the diseased subjects. While only minor differences were observed between the blood samples of the diseased and the healthy subjects regarding the TCR genes, CD5, HLA-DR and CD5+CD19 positive cells occurred in higher proportions in the blood samples of the subjects susceptible to periodontal disease than in healthy controls. It may be suggested that (i) TCR V alpha/Vbeta expression in peripheral blood samples of subjects with periodontal disease does not differ from that of healthy individuals, and (ii) the periodontitis lesion expresses a unique TCR repertoire in which the Vbeta 17 gene dominates.

Adult↗