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Biomedical subjects

A Tarkowski

Publications and source records attributed to A Tarkowski.

At least 55 records · Page 3Linked to original sources
PubMed2000

Prevention of diseases caused by Staphylococcus aureus using the peptide RIP.

Staphylococcus aureus causes many diseases including cellulitis, keratitis, osteomyelitis, septic arthritis and mastitis. The heptapeptide RIP has been shown to prevent cellulitis in mice, which was induced by S. aureus strain Smith diffuse. Here we show that RIP can also significantly reduce the overall pathology and delay the onset of disease symptoms in several other models of S. aureus infections, including: keratitis (tested in rabbits against S. aureus 8325-4), osteomyelitis (tested in rabbits against S. aureus MS), mastitis (tested in cows against S. aureus Newbould 305, AE-1, and environmental infections) and septic arthritis (tested in mice against S. aureus LS-1). These findings substantiate that RIP is not strain specific in its inhibitory activity and that RIP is an effective inhibitor of bacterial pathology at multiple body sites following diverse routes and doses of administration. These findings strongly evidence the potential value of RIP as a chemotherapeutic agent.

Animals↗
PubMed2000

Antigen-specific regulation of CD1 expression in humans.

During the last decade the CD1 family of cell surface glycoproteins has been implicated in the presentation of nonpeptide antigens in man. Recent findings by our group indicate that CD1 molecules also can be involved in the presentation of certain bacterial proteins. However, CD1a, b, and c (group 1 CD1 molecules) are not present at significant levels on circulating monocytes unless their expression is induced by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study we investigated the cell surface expression of CD1 molecules following the antigenic stimulation in vivo via immunization of healthy volunteers with tetanus toxoid vaccine and in vitro cell cultures using the same antigen. Both the in vivo and in vitro studies demonstrated clear up-regulation of the surface expression of CD1a, b, and c on monocytes as a result of antigenic stimulation with tetanus toxoid, supporting the idea that CD1 molecules participate in the presentation of this protein antigen in man. In vitro, antigen-triggered expression of these molecules was mediated by GM-CSF, since neutralization of this cytokine with specific antibody totally abrogated CD1a, b, and c expression. In contrast to the group 1 CD1 molecules, CD1d was found to be constitutively expressed on the majority of circulating monocytes and B lymphocytes prior to immunization. There was no effect of antigenic stimulation with tetanus toxoid on the cell surface expression of CD1d, suggesting major differences in regulation of the expression and function of the different CD1 molecules in humans. Altogether our results point to antigen-driven up-regulation of CD1a, b, and c expression on human monocytes that is mediated by GM-CSF and no effect on CD1d expression.

Adult↗
PubMed2000

An experimental model of cutaneous infection induced by superantigen-producing Staphylococcus aureus.

Skin infections caused by Staphylococcus aureus, such as erysipelas, are commonly occurring, painful, and costly for society. Despite the high prevalence of this condition, little is known about the host immune responsiveness and bacterial virulence factors during S. aureus dermatitis. We present here a mouse model of infectious dermatitis in which S. aureus is inoculated by an intracutaneous injection to the shaved back of NMRI mice. Visible skin inflammation, characterized by redness and swelling, was noted 48 h after inoculation of staphylococci in mice that received 2 x 108 colony-forming units of S. aureus. Microscopic evaluation revealed a dermal and subcutaneous infiltrate rich in macrophages and neutrophilic granulocytes already within 6 h after inoculation. A sparse influx of T lymphocytes was noted somewhat later. Bacterial cultures from skin revealed high numbers of staphylococci early after inoculation, with a successive decline during 2 wk follow-up. Total white blood cell count as well as the number of polymorphonuclear leukocytes peaked 2 d after bacterial inoculation. Also, serum interleukin-6 levels peaked within 2 d, with a 10-fold increase compared to non-infected control mice, indicating a systemic reaction to skin infection. The role of toxic shock syndrome toxin 1 in the pathogenesis of the dermatitis was assessed using isogenic S. aureus strains. Even though the gross inflammatory skin reaction was similar for mice infected with either of the strains, it was apparent that bacteria secreting toxic shock syndrome toxin 1 preferentially triggered influx of T lymphocytes to the skin. In addition, mice inoculated with staphylococci producing toxic shock syndrome toxin 1 showed a weight decrease during the experiment whereas mice inoculated with the isogenic strain showed a weight increase. This model of staphylococcal dermatitis will enable future in-depth studies regarding the host-bacterium relationship.

Animals↗
PubMed2000

Nuclear factor-kappa B is involved in the catecholaminergic suppression of immunocompetent cells.

Catecholamines are known to exert a powerful impact on the immune system by downregulation of proliferation and differentiation, and induction of apoptosis. However, the mechanism for this regulatory route is still unclear. Therefore well established human monocytic cell-lines and nontransformed human monocytes, obtained from peripheral blood, were incubated with an optimal concentration of LPS and varying concentrations of the catecholamine dopamine. The proliferative response to LPS was determined by [3H]thymidine incorporation, and a significant suppressive effect by dopamine was obtained. LPS-induced binding of NF-kappa B to DNA, determined by electrophoretic mobility shift assay, was inhibited by extrinsic dopamine, leading to a decreased proliferation and cytokine expression. In contrast, the intracellular ceramide concentration was not affected by incubation of peripheral blood lymphocytes with dopamine. Our findings suggest that the NF-kappa B-I-kappa B transcription machinery may well be involved in the catecholaminergic regulation of the immune system, while the ceramide-SAPK/JNK cascade appears not to play a significant role in this suppression.

B-Lymphocytes↗
PubMed2000

Role of neutrophil leukocytes in cutaneous infection caused by Staphylococcus aureus.

Despite the high prevalence of cutaneous infections, little is known about the role of host immune responsiveness during Staphylococcus aureus dermatitis. We have recently described a murine model of infectious dermatitis induced by superantigen-producing S. aureus. To assess the role of neutrophils in staphylococcal dermatitis, mice were given granulocyte-depleting monoclonal antibody prior to and on several occasions following intracutaneous inoculation with staphylococci. The granulocyte-depleted mice that had been intradermally inoculated with S. aureus developed crusted ulcerations which tended not to heal, whereas animals injected with control monoclonal antibody displayed only minor and transient skin lesions. The finding of severe ulcerations in neutropenic mice correlated with a significantly higher burden of bacteria in the blood and skin during the early phase of the infection. Importantly, while mice with an intact granulocyte population showed only limited skin infection, bacteremia occurred in the great majority of the neutrophil-depleted animals. As a consequence, the latter individuals exhibited significantly increased levels of the proinflammatory cytokine interleukin-6 and specific antibodies to staphylococcal cell wall components and toxic shock syndrome toxin-1 in the serum. Our data point to a crucial protective role of granulocytes in S. aureus dermatitis.

Animals↗
PubMed2000

Are B lymphocytes of importance in severe Staphylococcus aureus infections?

To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0. 0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course of S. aureus-induced septic arthritis.

Animals↗
PubMed2000

Autologous stem cell transplantation in a case of treatment resistant central nervous system lupus.

This case report describes a young woman with systemic lupus erythematosus starting at 16 years of age and giving rise to severe neurological complications including bilateral opticus neuritis and transverse myelitis. Despite heavy immunosuppression her condition steadily aggravated. At this point it was decided to perform autologous stem cell transplantation. Haematopoietic stem cells were mobilised with cyclophosphamide and granulocyte colony stimulating factor. Enrichment of CD34(+)cells was followed by depletion of peripheral T and B cells. The post-transplantation course was uneventful, and all the neurological deficits improved promptly during the 15 months of follow up. This is the first description of successful autologous stem cell transplantation in a case of life threatening central nervous system lupus.

Adolescent↗
PubMed2000

Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement.

Symptoms originating from central nervous system (CNS) are frequently occuring in patients with systemic lupus erythematosus (SLE). Reliable diagnostic markers for this condition are presently lacking. Importantly, CNS involvement in lupus patients is associated with increased morbidity and mortality. The aim of this retrospective evaluate was to study the diagnostic value of cerebrospinal fluid (CSF) cytokine levels in SLE patients with CNS involvement. 34 patients with SLE were hospitalized and investigated for the presence of CNS lupus. These patients were evaluated clinically and with magnetic resonance imaging (MRI) and CSF analyses, as well as with neuropsychiatric tests. 13 patients were found to have CNS lupus whereas another four of the patients fulfilled the criteria for CNS involvement but were excluded from this group due to other causes of CNS involvement. Lastly, in 17 SLE cases, the diagnosis of CNS lupus could not be confirmed. CSF levels of interleukin-6 (IL-6) and IL-8, as well as the CSF/serum IL-6 ratio, were elevated in the CNS lupus group, compared with the 17 SLE patients not fullfilling a diagnosis of cerebral lupus. Interestingly, follow-up of five patients being successfully treated for CNS lupus revealed profound decrease of intrathecal IL-6 levels. These results indicate that analysis of CSF cytokine levels, especially IL-6 and IL-8, may be useful in the diagnostics and possibly follow-up of SLE patients with cerebral lupus.

Adolescent↗
PubMed2000

The role of bacterial DNA in septic arthritis.

Unmethylated CpG motifs are frequently found in bacterial DNA and have recently been shown to exert immunostimulatory effects on leukocytes. Bacteria produce severe septic arthritis; bacterial DNA may be involved in this process. We injected intraarticularly bacterial DNA and oligonucleotides containing unmethylated CpG motifs into knee joints of mice. Arthritis was seen by histopathology within 2 h and lasted for at least 14 days, and was characterized by an influx of monocytic, Mac-1+ cells and by a lack of T lymphocytes. Macrophages and their products such as tumor necrosis factor (TNF) alpha are essential for development of arthritis triggered by bacterial DNA containing CpG motifs. In contrast, neurophils, NK cells, and T/B cells were not instrumental in this condition. This review demonstrates that bacterial DNA containing unmethylated CpG motifs induces arthritis and indicates an important pathogenic role for bacterial DNA in septic arthritis.

Animals↗
PubMed2000

Preventing staphylococcal disease by disarming the immune responses to infection.

Use of experimental models of staphylococcal infections clarified several bacterial virulence factors as well as many hematopoetic cell types and their products that are involved in the pathogenesis of infection. For many decades it has been believed that antibody mediated response to staphylococci and their products was the major, if not the only one, hallmark of immune reactivity during infection. Recent studies have documented that T cell mediated responses to superantigens produced by staphylococci are not only prominent but also decisive with respect to sequels. Also the nonantigen specific immune responsiveness to staphylococcal infection is reviewed including roles of neutrophils, complement system and nitric oxide. The knowledge gained regarding staphylococcal virulence factors and the host immune responses has prompted researchers to develop new strategies how to interact in vivo witl the infectious process. Some of these approaches are commented in this review regarding e.g. vaccination procedures in order to prevent severe infections as well as therapeutic procedures to minimize organ damage during an ongoing infectious process.

Animals↗
PubMed1999

Outcome of Staphylococcus aureus-triggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host.

Disruption of the IL-4 gene in two inbred mouse strains revealed a dual role of IL-4 in Staphylococcus aureus sepsis and arthritis depending on the host's genetic background. IL-4 was protective in 129SV mice, since 5 days after S. aureus inoculation IL-4(-/-) mice displayed 70% mortality as compared to survival of all 129SV wild-type counterparts. On the other hand, IL-4 was detrimental in C57BL/6 mice, since survival of IL-4(-/-) C57BL/6 mice was increased, as compared to wild-type controls, due to decreased staphylococcal growth. Altogether, our results show the dual role of IL-4 in S. aureus sepsis and arthritis, depending on the genetic background of the host.

Animals↗
PubMed1999

Treatment of experimental autoimmune arthritis by nasal administration of a type II collagen-cholera toxoid conjugate vaccine.

OBJECTIVE: To assess the efficacy of intranasal administration of microgram amounts of type II collagen (CII) coupled to cholera toxin B subunit (CTB) with respect to the development of collagen-induced arthritis, even when given after the onset of clinically evident arthropathy. METHODS: DBA/1 mice were immunized with CII to induce arthritis and were subsequently treated with CTB-CII, CTB-conjugated ovalbumin, or CII alone. The incidence and severity of arthritis were assessed clinically and histologically. RESULTS: Treatment with CTB-CII conjugate effectively suppressed leukocyte infiltration into the synovium and prevented bone erosion. Comparable doses of unconjugated CII administered by the same route were relatively ineffective. Protection with nasal CTB-CII vaccine was associated with decreased production of interleukin-4 (IL-4), IL-6, and interferon-gamma and with reduced CII-specific IgG1 and IgG2a antibody responses in regional lymph nodes. CONCLUSION: Nasal treatment with CTB-CII appears to result in decreased peripheral Th1 and Th2 responses to collagen. These results suggest that intranasal vaccination with CTB-CII may offer an effective immunotherapeutic means for the control of chronic polyarthritis.

Administration, Intranasal↗
PubMed1999

Integrin-associated protein (IAP)-deficient mice are less susceptible to developing Staphylococcus aureus-induced arthritis.

The integrin-associated protein (IAP) has been shown to function in a signaling complex with beta3 integrins, influencing the migration of phagocytic cells into inflamed tissues. We have previously shown that gene-targeted mice deficient for IAP succumbed to peritonitis when inoculated with gram-negative bacteria. The aim of this study was to assess the role of IAP in our recently established model of haematogenously induced Staphylococcus aureus septicaemia and arthritis. In this model, neutrophils play a crucial role in the early phase of the infection. Mice lacking IAP and congenic controls were intravenously inoculated with S. aureus LS-1. The IAP-/- mice were resistant to developing clinical signs of arthritis compared with their IAP-expressing littermates. The clinical findings were corroborated by histopathological evaluation indicating that the IAP-/- mice had less cartilage and bone destruction in the joints. We believe that a delayed migration of leukocytes into the joints of mice lacking IAP expression leads to decreased susceptibility to develop S. aureus-induced arthritis.

Animals↗
PubMed1999

Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia.

The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1 beta, IL-6, TNF-alpha, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF-alpha on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF-alpha compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF-alpha and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF-alpha-exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF-alpha in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF-alpha exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.

Aged↗
PubMed1999

Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis.

Unmethylated CpG motifs are often found in bacterial DNA, and exert immunostimulatory effects on hematopoietic cells. Bacteria produce severe joint inflammation in septic and reactive arthritides; bacterial DNA may be involved in this process. We injected bacterial DNA originating from Escherichia coli and Staphylococcus aureus and oligonucleotides containing CpG directly into the knee joints of mice of different strains. Arthritis was seen by histopathology within 2 hours and lasted for at least 14 days. Unmethylated CpG motifs were responsible for this induction of arthritis, as oligonucleotides containing these motifs produced the arthritis. The arthritis was characterized by an influx of monocytic, Mac-1+ cells and by a lack of T lymphocytes. Depletion of monocytes resulted in abrogation of the synovial inflammation. Tumor necrosis factor (TNF)-alpha, a cytokine produced by cells of the monocyte/macrophage lineage, is an important mediator of this disease, as expression of mRNA for TNF-alpha was evident in the inflamed joints, and the CpG-mediated inflammation was abrogated in mice genetically unable to produce this cytokine. These findings demonstrate that bacterial DNA containing unmethylated CpG motifs induces arthritis, and indicate an important pathogenic role for bacterial DNA in septic arthritis.

Animals↗
PubMed1999

Complement depletion aggravates Staphylococcus aureus septicaemia and septic arthritis.

The aim of the study was to assess the role of the complement system in Staphylococcus aureus arthritis and septicaemia. The murine model of haematogenously acquired septic arthritis was used, injecting intravenously toxic shock syndrome toxin-1 (TSST-1), producing S. aureus LS-1. Complement was depleted using cobra venom factor (CVF). Evaluation of arthritis was performed clinically and histopathologically. In addition, the effect of complement depletion on the phagocytic activity of leucocytes was assessed in vivo and in vitro. Six days after inoculation of S. aureus the prevalence of arthritis in decomplemented mice was three-fold higher than that in controls (91% versus 25%). The clinical severity of arthritis at the end of the experiment, expressed as arthritic index, was 7.3 and 1.9, respectively. These findings were confirmed by histological index of synovitis as well as of cartilage and/or bone destruction being significantly higher in decomplemented mice than in controls (9.8 +/- 1.7 versus 4.9 +/- 1.2, P < 0.05; and 7.9 +/- 1.7 versus 3.0 +/- 0.9, P < 0.05, respectively). Also, the septicaemia-induced mortality was clearly higher in decomplemented mice compared with the controls. CVF treatment significantly reduced in vivo polymorphonuclear cell-dependent inflammation induced by subcutaneous injection of olive oil and mirroring the capacity of polymorphonuclear cells (PMNC) to migrate and/or extravasate. Besides, the decomplementation procedure significantly impaired phagocytic activity of peripheral blood leucocytes in vitro, since the number of phagocytes being able to ingest bacteria decreased by 50% when the cells were maintained in decomplemented serum compared with those in intact serum. The conclusion is that complement depletion aggravates the clinical course of S. aureus arthritis and septicaemia, possibly by a combination of decreased migration/extravasation of PMNC and an impairment of phagocytosis.

Animals↗
PubMed1999

Protective role of NK1.1+ cells in experimental Staphylococcus aureus arthritis.

In a model of Staphylococcus aureus-induced septic arthritis in C57Bl/6 mice we investigated the role of natural killer (NK) cells in the development of disease. Depletion of NK1.1+ cells was achieved by repeated injections of the PK136 antibody, whereas control mice received an irrelevant monoclonal antibody, O1C5.B2. Both groups of mice then received injections intravenously with 2 x 107 live S. aureus LS-1 secreting toxic shock syndrome toxin-1 (TSST-1). The mice were evaluated for 16 days with regard to weight, mortality and arthritis. Nine days after bacterial injection, 9/19 mice depleted of NK cells had developed arthritis compared with 1/17 in the control group (P = 0.01). The experiment was repeated twice with the same outcome. NK cell-depleted and control mice displayed the same degree of histopathological signs of arthritis at day 16. Depletion of NK cells did not affect uptake of bacteria by phagocytic cells in vitro, or bacterial clearance in vivo. In NK cell-depleted mice there was a tendency to increased levels of antibodies to TSST-1, whereas total immunoglobulin levels were similar to those in controls. NK cell depletion of non-infected mice did not affect the magnitude of inflammatory response during the T cell-dependent cutaneous DTH reaction to oxazolone, or during granulocyte-mediated inflammation. However, specific antibody responses to oxazolone were greatly increased in depleted animals. In conclusion, our study demonstrates that NK cells protect against arthritis during S. aureus infection. This outcome does not seem to be due to an influence on bacterial clearance, but could be due to an interaction with the host anti-inflammatory mechanisms.

Animals↗