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A Tarkowski

Publications and source records attributed to A Tarkowski.

At least 91 records · Page 5Linked to original sources
PubMed1998

Granulocyte-macrophage colony-stimulating factor in Staphylococcus aureus-induced arthritis.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that is able to increase not only the production of phagocytic cells but also their efficacy with respect to, e.g., bactericidal properties. In this study, we wanted to analyze the impact of GM-CSF on experimental Staphylococcus aureus-induced arthritis. For that purpose, mice were administered GM-CSF before and after bacterial inoculation. Although there was an increase in the total number of leukocytes as well as in the granulocyte fraction, there was no favorable effect on the severity of arthritis or on survival rates. There were no obvious differences between the GM-CSF-pretreated animals and controls with regard to growth of staphylococci in joints and kidneys 4 days after the bacterial inoculation. In contrast, mice that had been pretreated with GM-CSF prior to bacterial inoculation showed approximately four times lower numbers of bacteria in their blood 24 h later. These results, along with those of our previous studies, suggest that on the one hand the granulocyte is the main protective cell during the course of S. aureus infection but that on the other hand, upregulation of granulocyte-macrophage production will not exert any additional protective effects with respect to tissue injury.

Animals↗
PubMed1998

Virulence factors of Staphylococcus aureus strains causing infective endocarditis--a comparison with strains from skin infections.

The objective was to study potential bacterial virulence factors in S. aureus endocarditis. S. aureus strains isolated from patients with well-classified episodes of infective endocarditis (IE) (n=26) were compared with control S. aureus strains from consecutive patients with skin infections (n=30). The potential virulence factors studied were Staphylococcal enterotoxin A-D (SEA, SEB, SEC, SED) and toxic shock syndrome toxin-1 (TSST-1) production and binding capacity to the extracellular matrix proteins: fibronectin, collagen type I, collagen type II and bone sialoprotein (BSP). None of the potential virulence factors studied was more prevalent among the IE strains. BSP binding was more often found in the control group with skin infections. Endocarditis patients with previous damage of the heart valves were more often infected by strains not producing any enterotoxin. No correlation was found between the potential bacterial virulence factors studied and IE. Concerning the toxins known to act as superantigens (SEA-E and TSST-1), the tendencies in this and other studies indicate that a larger study group might identify them as pathogenic factors in a subgroup of staphylococcal endocarditis.

Adolescent↗
PubMed1997

Suppression of type II collagen-induced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol.

OBJECTIVE: To evaluate the antiarthritic properties of 2-methoxyestradiol, an endogenous metabolite of estradiol, on type II collagen-induced arthritis (CIA) in DBA/1 mice. METHODS: The effects of treatment with 2-methoxyestradiol on the development of CIA were evaluated clinically and histologically. The in vitro effects of 2-methoxyestradiol on lymphocyte and endothelial cell proliferation and differentiation were analyzed by standard methods. RESULTS: The development of CIA was significantly suppressed by 2-methoxyestradiol. Incubation with 2-methoxyestradiol suppressed the in vitro proliferation of endothelial cells, indicating that this compound down-regulates angiogenesis. Endothelial cell production of nitric oxide (NO) was also down-regulated by 2-methoxyestradiol. In contrast to estradiol, 2-methoxyestradiol exerted neither detectable feminizing effects on the sex organs nor inhibition of leukocyte development in hematopoietic organs. CONCLUSION: The development of CIA is suppressed by 2-methoxyestradiol, possibly via inhibition of angiogenesis. Diminished NO production could be of importance in vivo because it is a potent proinflammatory mediator. Since 2-methoxyestradiol exerts only mild side effects compared with estradiol, it is an interesting candidate for therapeutic use in inflammatory diseases.

2-Methoxyestradiol↗
PubMed1997

Measurements of catecholamine-mediated apoptosis of immunocompetent cells by capillary electrophoresis.

Single cell analysis with capillary electrophoresis, a technique capable of detecting zeptomole quantities (10(-21) mole) of neurochemical species, has been used to demonstrate that lymphocytes are capable of active synthesis of dopamine and norepinephrine. Exposure of lymphocytes to catecholamines at concentrations as low as 10 nM leads to decreased proliferation and differentiation, e.g. interferon-gamma (IFN-gamma), interleukin-4 (IL-4) and immunoglobulin (Ig). In addition, both inhibition of dopamine uptake with nomifensine and inhibition of packing of catecholamines into vesicles with tetrabenazine, results in significantly lower levels of dopamine and norepinephrine (p < 0.01 and p < 0.05, respectively). The catecholamine-dependent inhibition of T- and B-lymphocyte activity is mediated via an induction of a Bcl-2/Bax and Fas/FasL involved apoptosis. These findings indicate a novel mechanism for regulation of lymphocyte activity in the central nervous system, whereby elevated regional levels of catecholamines might lead to the immunoprivilege of the brain.

Adrenergic Uptake Inhibitors↗
PubMed1997

Oligoclonal expansion of muscle infiltrating T cells in inclusion body myositis.

Inclusion body myositis (IBM) is the most common muscle disease affecting individuals over 50 years of age. An important feature of IBM is invasion of muscle fibers by T cells. The muscle infiltrating T cells show a restricted usage of variable (V) alpha/beta gene families. In this study we have investigated the clonality of T cells using two of the predominant V beta families i.e. V beta 3 and V beta 8 in three patients with IBM. The study was performed by reverse transcription and polymerase chain reaction (RT-PCR) analysis, followed by cloning and sequencing of the T cell receptor complementarity determining region 3. We found oligoclonal expansion of V beta 3 bearing muscle infiltrating T cells in two patients and of V beta 8 in one patient, supporting the concept that antigen stimulated T cells are important in the pathogenesis of IBM. Results of HLA typing indicated a genetic predisposition for the disease by the presence of DR3, DR52 and DQB1*0201/0202 in all three patients.

Aged↗
PubMed1997

Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis.

The aim of this study was to assess the role of NO and its metabolites in bacterial arthritis. The murine model of haematogenously acquired septic arthritis was used. Swiss mice treated with NOS inhibitors (N(G)-monomethyl-L-arginine or N(omega)-nitro-L-arginine methyl ester) were injected intravenously with toxic shock syndrome toxin-1 (TSST-1) producing Staphylococcus aureus LS-1. Arthritis was evaluated clinically and histopathologically. Serum cytokine levels, bacterial isolates and intracellular capacity of macrophages to kill bacteria were also analysed. The frequency of arthritis in mice treated with NOS inhibitors was three to four-fold higher than that in non-treated controls (75% versus 20%). The severity of arthritis, expressed as mean arthritic index, was 1.4 and 0.4, respectively. Cartilage and/or bone destruction occurred in 63% of NOS inhibitor-treated mice, but only in 10% of controls. Also, the cumulative septicaemia-induced mortality was clearly higher in mice treated with NOS inhibitors compared with non-treated controls. Intracellular killing capacity of the peritoneal macrophages, treated in vitro with NOS inhibitors, was decreased. Thus, 24 h after bacterial inoculation peritoneal macrophages pretreated with NOS inhibitors killed more than 10 times less bacteria than the control ones (P<0.01). We conclude that NOS inhibitors aggravate S. aureus arthritis, possibly by inducing impairment of the intracellular killing capacity of macrophages.

Animals↗
PubMed1997

Intrathecal release of pro- and anti-inflammatory cytokines during stroke.

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL-1beta and IL-6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0-3, 7-9, 21-26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL-8 and GM-CSF, and on day 3 for the immunoregulatory cytokine IL-10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL-8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor-alpha (TNF-alpha) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.

Adult↗
PubMed1997

Induction of selective anergy by toxic shock syndrome toxin-1 in CD8+ T cells.

Interferon-gamma (IFN-gamma) mRNA expression of murine splenic CD8+ T cells in response to toxic shock syndrome toxin-1 (TSST-1) was examined in vitro. In primary response to TSST-1, purified CD8+ cells expressed a low frequency of IFN-gamma mRNA and produced very little interleukin-2 (IL-2) compared with unseparated lymphocytes and purified CD4+ cells. The addition of IL-2 to the cell culture enhanced IFN-gamma mRNA expression in the CD8+ population. Upon restimulation with TSST-1, no IL-2 production and hardly any IFN-gamma mRNA expression were observed in the purified CD8+ lymphoblasts. Exogenously added IL-2 did not increase the IFN-gamma mRNA expression in purified CD8+ blasts exposed to TSST-1. In contrast, stimulation with concanavalin A induced a high frequency of IFN-gamma mRNA in purified CD8+ blasts. Moreover, TSST-1 induced strong IFN-gamma mRNA expression in unseparated T lymphoblasts and purified CD4+ populations. Interestingly, a combined immunocytochemistry and in situ hybridization technique showed a high frequency of CD8+ IFN-gamma mRNA-expressing cells in an unseparated blast population. These results demonstrate that TSST-1 induces a selective anergy within the purified CD8- T-cell compartment and that the IFN-gamma mRNA expression in CD8+ T blasts can be achieved by stimulation of unseparated T cells with TSST-1.

Animals↗
PubMed1997

Beneficial effect of glucocorticoids on the course of haematogenously acquired Staphylococcus aureus nephritis.

The effect of combined antibiotic and corticosteroid treatment on the course of haematogenously acquired Staphylococcus aureus nephritis was studied. Mice were given a single injection of S. aureus producing toxic shock syndrome toxin-1 in a dose capable of inducing a high frequency of inflammatory kidney lesions and divided into three groups according to a treatment regimen. In all untreated animals inflammatory infiltrates were seen in kidney cortex and medulla with high frequencies of glomerular (90%) and tubular damage (50%) as well as fibrotic changes (50%). The treatment with antibiotics alone reduced significantly only the occurrence of focal inflammatory infiltrates. In contrast, the mice treated with a combination of antibiotics and corticosteroids displayed in 64% of cases normal histological kidney appearance and a significant decrease in occurrence of glomerular (P<0.01) and tubular (P<0.05) lesions. Immunohistochemically, the combined treatment resulted in a more pronounced decrease in numbers of CD4, IL-2R (four to fivefold) and CD8 positive cells in kidney inflammatory lesions compared to antibiotics only treated group. Thus, glucocorticoids in association with antibiotics are shown to improve the outcome of septic murine nephritis, possibly due to suppression of kidney infiltrating T cells.

Animals↗
PubMed1997

Major histocompatibility complex class II region confers susceptibility to Staphylococcus aureus arthritis.

The importance of the MHC class II region for the development of septic arthritis was studied in a murine model of haematogenously induced Staphylococcus aureus arthritis. In the first experiment MHC class II deficient mice (A beta-/-) and their heterozygous (A beta+/-) littermates were intravenously inoculated with a single dose of toxic shock syndrome toxin-1 producing S. aureus LS-1 strain. The results demonstrate that the expression of class II MHC molecules increases the prevalence and severity of arthritis. To analyse the impact of MHC class II haplotypes on the disease onset and progression the authors used congenic C3H.NB, C3H.Q and C3H/HeJ mice in the second set of experiments. The results show that C3H/HeJ mice developed the highest frequency and the most severe course of arthritis compared with C3H.NB and C3H.Q animals. Immunohistochemical analysis of arthritic joints revealed equal number of macrophages, CD4+ and CD8+ lymphocytes in the inflamed synovia in all the congenic mice. In contrast, the number of MHC class II expressing cells was higher in the arthritic joints of C3H/HeJ mice compared with the congenic strains (P < 0.001). Furthermore, serum levels of proarthrtitogenic cytokines, such as tumour necrosis factor and interleukin-6 were higher in C3H/HeJ group. This study indicates that MHC class II expression is necessary for the development of S. aureus arthritis in mice and that different MHC class II haplotypes confer varying susceptibility for development of joint inflammation induced by staphylococci.

Animals↗
PubMed1997

Differential immunological aberrations in patients with primary and secondary Sjögren's syndrome.

The aim of the present study was to analyse possible differences in immunological features between patients with primary and secondary Sjögren's syndrome (SS). Ten patients with primary SS and 10 patients with secondary SS also suffering from rheumatoid arthritis, were identified according to established criteria for SS. Ten healthy, age-matched women served as controls. The authors analysed the phenotypic characteristics of lymphocytes in peripheral blood as well as in focal inflammatory infiltrates of minor salivary gland biopsies. Functional analyses of T lymphocytes were performed after stimulation with mitogens and antigen. B cell activity was determined at the single cell level by spontaneous and mitogen induced immunoglobulin production. Serum levels of IL-4, IL-6 and IFN-gamma were also analysed. Patients with primary SS displayed a significantly higher degree of salivary gland inflammation and reduced salivary flow than did patients with secondary SS. Decreased in vitro T cell responses to antigen and mitogens were evident in both patient groups. The CD4/CD8 ratios in both peripheral blood and salivary gland lesions were significantly lower in primary SS compared with secondary SS patients. Polyclonal B cell activation, measured as the frequency of spontaneous immunoglobulin producing cells, was most prominent in primary SS, whereas a diminished response to poke-weed mitogen (PWM), a T cell dependent B cell mitogen, was more pronounced in secondary SS. The results reveal certain immunological aberrations in the whole group of patients with SS. In addition, the authors demonstrated distinct differences in immune dysfunction between patients with primary and secondary SS, indicating that they may constitute separate entities.

Adult↗
PubMed1997

The role of staphylococcal polysaccharide microcapsule expression in septicemia and septic arthritis.

Staphylococcus aureus arthritis is a rapidly progressive and highly erosive disease of the joints in which both host and bacterial factors are of pathogenic importance. One potential bacterial virulence factor is the ability to express a polysaccharide capsule (CP). Among 11 reported capsular serotypes, CP type 5 (CP5) and CP8 comprise 80 to 85% of all clinical blood isolates. The aim of this study was to assess the role of CP5 as a virulence factor in staphylococcal septicemia and septic arthritis with a recently established murine model of hematogenously spread S. aureus arthritis. NMRI mice were inoculated intravenously with S. aureus strains isogenic for expression of CP5, and clinical, bacteriological, serological, and histopathological progression of disease was studied. Inoculation of 7 x 10(6) CFU of S. aureus per mouse induced 55% mortality in the group inoculated with the CP-expressing bacteria, compared to 18% in the group inoculated with CP- mutants. A lower dose of inoculum (3 x 10[6] per mouse) did not give rise to mortality in mice inoculated with CP mutant strains, whereas 18% of the mice inoculated with the CP5-expressing S. aureus died. Importantly, mice inoculated with S. aureus expressing CP5 had a significantly higher frequency of arthritis and a more severe form of the disease. In vitro assays suggested that macrophages were not able to phagocytize CP5+ staphylococci as efficiently as they were CP5- strains. In addition, once phagocytized, CP5+ bacteria were less efficiently killed than CP- mutants. In summary, CP5 leads to a higher frequency of arthritis and a more severe course of the disease. This seems to be related to the effects of the downregulatory properties of CP on the ingestion and intracellular killing capacity of phagocytes. Our results clearly indicate that the expression of CP5 is a determinant of the virulence of S. aureus in arthritis and septicemia.

Animals↗
PubMed1997

Role of neutrophils in experimental septicemia and septic arthritis induced by Staphylococcus aureus.

We have previously described a murine model of hematogenously induced Staphylococcus aureus sepsis and arthritis. In this model, large numbers of granulocytes can be observed both in the circulation and locally in the inflamed synovium within 24 h after bacterial inoculation. To assess the role of neutrophils in this severe infection, mice were given granulocyte-depleting monoclonal antibody RB6-8C5 before being inoculated with S. aureus. All the control mice survived their intravenous injection with 3 x 10(7) CFU of S. aureus, whereas all the mice given RB6-8C5 antibody died of sepsis within 2 to 3 days. Even when the inoculum size was reduced sixfold (i.e., 6 x 10(6) CFU/mouse), 50% of the RB6-8C5-treated animals died within 6 days. The RB6-8C5-treated mice had a significantly higher burden of bacteria in their blood and kidneys 24 and 48 h after bacterial inoculation. In addition, when a suboptimal dose of bacteria was administered, the neutrophil-depleted animals displayed a higher frequency of arthritis than did the controls. The granulocyte-depleted animals exhibited increased levels of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-6, and gamma interferon, reflecting the severity of their disease. This is the first direct demonstration of neutrophils playing a crucial protective role in the early phase of S. aureus infection.

Animals↗
PubMed1997

Fasting enhances mucosal antigen specific B cell responses in rheumatoid arthritis.

OBJECTIVE: To evaluate the influence of fasting on the antigen specific immune responsiveness in patients with rheumatoid arthritis and healthy volunteers. METHODS: Seven rheumatoid arthritis patients and 17 healthy volunteers were immunised perorally or parenterally with influenza virus vaccine after a three to six day long period of total energy deprivation (water fast). The subsequent antigen specific antibody mediated immune response was recorded in the blood at the single cell level by the ELISPOT method. RESULTS: Short term starvation induced an enhanced antigen specific mucosa derived B lymphocyte response in rheumatoid arthritis patients and healthy volunteers. In contrast, the systemic B cell responses were not significantly altered by a total energy deprivation. CONCLUSIONS: Short term starvation increases the mucosa derived B cell responsiveness, while systemic responsiveness is largely unaffected. The similar pattern of response in rheumatoid arthritis patients and healthy volunteers indicates that fasting alters the mucosal immune response independently of medical treatment.

Administration, Oral↗
PubMed1996

In situ hybridization analysis of synovial and systemic cytokine messenger RNA expression in superantigen-mediated Staphylococcus aureus arthritis.

OBJECTIVE: To investigate patterns of synovial and systemic cytokine messenger RNA (mRNA) expression in mice with superantigen-mediated Staphylococcus aureus arthritis. METHODS: Mice were inoculated intravenously with 1 x 10(7) colony-forming units of toxic shock syndrome toxin-1-producing S aureus LS-1. Synovial tissues and spleens were obtained at varying time intervals after bacterial inoculation, and examined for mRNA expression of interleukin-1beta (IL-1beta), IL-4, IL-10, IL-12, tumor necrosis factor alpha (TNFalpha), TNFbeta, interferon-gamma (IFN-gamma), transforming growth factor beta, and perforin, by an in situ hybridization technique. RESULTS: In situ hybridization revealed early synovial up-regulation of TNFalpha and IL-1 beta mRNA expression. Peak frequencies of these proinflammatory cytokines were observed at the second and third week of the infection. Expression of T cell-derived cytokine mRNAs was detected later, and in a relatively low frequency. Notably, induction and peak numbers of Th2 cytokine (IL-4 and IL-10) mRNA expression preceded Th1 cytokine (IFNgamma and TNFbeta) mRNAs. In comparison with synovial tissues, peak spleen cytokine mRNA expression of IL-1beta, TNFalpha, TNFbeta, IL-12, and IFNgamma occurred earlier, but displayed a clearly lower magnitude of expression. CONCLUSION: These findings demonstrate synovial and systemic up-regulation of cytokine mRNA expression during S aureus arthritis, indicating that both monocyte/macrophage and T cell-derived products are involved in the pathogenesis of this disease.

Animals↗
PubMed1996

Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis.

OBJECTIVE: To evaluate the combined effect of systemic corticosteroid and antibiotic therapy on the course of septic arthritis. METHODS: The murine model of hematogenously acquired Staphylococcus aureus arthritis was used. Mice were treated with corticosteroids and antibiotics, and were followed up individually. Arthritis was evaluated clinically and histopathologically. Serum samples and bacterial isolates were also analyzed. RESULTS: The prevalence of arthritis 14 days after the onset of the disease was 22% in the corticosteroid and antibiotic-treated group, as compared with 81% in the control (nontreated) group and 48% in the antibiotic-treated group. The severity of arthritis also decreased in the corticosteroid and antibiotic-treated group, as did the mortality rate. Immunohistochemical analysis revealed a dramatic decrease in T cells and macrophages in the synovium of mice that took the combined therapy. The mechanisms leading to this outcome include the inhibitory effect of corticosteroids on T cell and B cell proliferation and differentiation, such as suppression of interferon-gamma (IFN gamma) production. Serum levels of IFN gamma were decreased 4-fold in the antibiotic-treated group compared with the controls; a 15-fold decrease was observed in the corticosteroid and antibiotic-treated animals. In addition, serum NO3- was significantly decreased in mice treated with antibiotics (P < or = 0.05), as well as in mice treated with corticosteroids and antibiotics (P < or = 0.001). CONCLUSION: Systemic corticosteroid administration along with antibiotic therapy had beneficial effects on the course and outcome of S aureus arthritis.

Adrenal Cortex Hormones↗
PubMed1996

Lateralization of cutaneous inflammatory responses in patients with unilateral paresis after poliomyelitis.

Unilateral paresis remaining after poliomyelitis may affect the expression of inflammatory diseases by lateralization of the disease manifestations. The purpose of this study was to assess the impact of the unilateral paresis after poliomyelitis on lateralization of neurogenic inflammation and immune responsiveness. The delayed-type hypersensitivity (DTH) reaction to tuberculin was used as an in vivo measure of antigen-specific T lymphocyte reactivity. Assessment of axon reflex vasodilatation was simultaneously employed to test for neurogenic inflammation. Fourteen of the 16 polio patients displayed a positive DTH reaction to tuberculin. All but two showed weaker DTH reaction on the paretic- compared to the contralateral-side (P = 0.001). Magnitude of electrically evoked axon reflexes significantly correlated to asymmetries of DTH responses. We conclude that damage of lower motor neuron leads to ipsilateral down-regulation of T cell-mediated cutaneous inflammation. This lateralization of DTH responses is related to deficiencies in motor and sympathetic innervation of the paretic extremity.

Adult↗