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Biomedical subjects

Georg Stingl

Publications and source records attributed to Georg Stingl.

At least 19 recordsLinked to original sources
PubMed2006

Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma.

PURPOSE: The recent identification of toll-like receptors (TLRs) and respective ligands allows the evaluation of novel dendritic cell (DC) -activating strategies. Stimulation of TLR9 directly activates human plasmacytoid DCs (PDCs) and indirectly induces potent innate immune responses in preclinical tumor models. We performed an open-label, multicenter, single-arm, phase II pilot trial with a TLR9-stimulating oligodeoxynucleotide in melanoma patients. PATIENTS AND METHODS: Patients with unresectable stage IIIb/c or stage IV melanoma received 6 mg PF-3512676 weekly by subcutaneous injection for 24 weeks or until disease progression to evaluate safety as well as clinical and immunologic activity. Clinical and laboratory safety assessments were performed weekly; blood samples for immunological measurements were taken every 8 weeks. Tumor measurements were performed according to Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty patients received PF-3512676 for a mean of 10.9 weeks with a mean of 10.7 injections. Laboratory and nonlaboratory adverse events were limited, transient, and did not result in any withdrawals. Two patients experienced a confirmed partial response; one response is ongoing for 140+ weeks. Three patients experienced stable disease. Immunologic measurements revealed induction of an activated phenotype of PDC, elevation of serum levels of 2',5'-oligoadenylate, a surrogate marker of type I interferon production, and significant stimulation of natural killer cell cytotoxicity (the latter was associated with clinical benefit). CONCLUSION: These results indicate that TLR9-targeted therapy can stimulate innate immune responses in cancer patients, identify biomarkers that may be associated with TLR9-induced tumor regression, and encourage the design of follow-up studies to evaluate the ability of this therapeutic approach to target human cancer.

Adult↗
PubMed2006

Soluble FAS ligand: a discriminating feature between drug-induced skin eruptions and viral exanthemas.

The clinical spectrum of cutaneous eruptions comprises benign variants like maculopapular rashes (MPRs) and potentially life-threatening events such as toxic epidermal necrolysis (TEN). Apoptosis of keratinocytes is a common histopathological feature of all these drug eruptions. As in skin lesions of TEN and Stevens-Johnson syndrome patients, apoptosis of keratinocytes is often accompanied by an only sparse cellular infiltrate, a soluble fatty acid synthetase ligand (sFASL)-mediated mechanism of keratinocyte cell death is postulated. In MPR patients, evidence for the occurrence of a similar process could not be established so far. We therefore examined sera and lesional skin sections from patients with clinical variants of drug eruptions for FASL expression using a sandwich ELISA and immunohistochemistry, respectively. As controls, healthy persons and patients with other inflammatory skin diseases such as viral exanthema were analyzed. Elevated levels of FASL were detected not only in TEN patients but also in sera and lesional skin of patients with MPR. In contrast, sFASL was repeatedly negative in all viral exanthemas and healthy controls tested. Thus, determination of sFASL serum concentration may represent a discriminating tool between drug rashes and viral exanthemas.

Acute Disease↗
PubMed2006

Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses.

Sphingosine 1-phosphate (S1P) levels in cells and, consequently, its bioactivity as a signalling molecule are controlled by the action of enzymes responsible for its synthesis and degradation. In the present report, we examined alterations in expression patterns of enzymes involved in S1P-metabolism (sphingosine kinases including their splice variants, sphingosine 1-phosphate phosphatases, and sphingosine 1-phosphate lyase) under certain inflammatory conditions. We found that sphingosine kinase type 1 (SPHK1) mRNA could be triggered in a cell type-specific manner; individual SPHK1 splice variants were induced with similar kinetics. Remarkably, expression and activity of S1P phosphatase 2 (SPP2) was found to be highly upregulated by inflammatory stimuli in a variety of cells (e.g., neutrophils, endothelial cells). Bandshift analysis using oligonucleotides spanning predicted NFkappaB sites within the SPP2 promoter and silencing of NFkappaB/RelA via RelA-directed siRNA demonstrated that SPP2 is an NFkappaB-dependent gene. Silencing of SPP2 expression in endothelial cells, in turn, led to a marked reduction of TNF-alpha-induced IL-1beta mRNA and protein and to a partial reduction of induced IL-8, suggesting a pro-inflammatory role of SPP2. Notably, up-regulation of SPP2 was detected in samples of lesional skin of patients with psoriasis, an inflammatory skin disease. This study provides detailed insights into the regulation of SPP2 gene expression and suggests that SPP2 might be a novel player in pro-inflammatory signalling.

Binding Sites↗
PubMed2006

Automated measurement of skin prick tests: an advance towards exact calculation of wheal size.

BACKGROUND: Using the Khoros image processing software environment, we developed a software-based system capable of extracting wheal size from skin prick tests (SPTs) in mm(2) for research and routine purposes. METHODS: At 20 min, the outlines of up to 20 wheals were marked with a pen and transferred with translucent adhesive tapes to a white paper form carrying predefined markings. The form was scanned at 200 dpi. The software automatically analysed the scanned image and calculated the sizes of the wheals. In a pilot study, serial SPTs with histamine in increasing dilutions were performed in 12 healthy volunteers in duplicate on both volar forearms. We matched the application results with a reference created from the scanned pictures. RESULTS: Bland-Altman analysis showed reference and software calculation reaching very high agreement. The comparison of reference/software resulted in a low centred coefficient of variation (COV) of 11.9%. This was superior to the conventional measurement of horizontal (COV 37.9%) or maximal/minimal diameter (COV 25.9%). CONCLUSION: We present an accurate tool for exactly calculating SPT wheal size in mm(2).

Adult↗
PubMed2006

Clinical Experience Acquired with Raptiva (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from extended treatment in an international, Phase III, placebo-controlled trial.

BACKGROUND: The 12-week, double-blind, placebo-controlled, first-treatment (FT) CLEAR trial period demonstrated the efficacy/safety of efalizumab in moderate-to-severe plaque psoriasis, including refractory or contraindicated patients unsuitable for other systemic treatments. This study assessed the efficacy/safety of open-label extended treatment (up to 24 weeks' continuous treatment) in patients not achieving > or =75% improvement in Psoriasis Area and Severity Index (PASI-75) at week 12 of the FT period. Time to relapse after treatment cessation, and efficacy/safety of 12 weeks' open-label re-treatment in patients achieving PASI-75 at week 12 FT were also assessed. PATIENTS AND METHODS: Patients with PASI-75 at week 12 FT were observed without treatment until relapse, then re-treated with open-label efalizumab (1.0 mg/kg/week for 12 weeks). Others received open-label extended treatment without intervening observation. RESULTS: Among efalizumab-treated patients (n = 308) who had < 75% PASI improvement at week 12 FT, extended treatment led to PASI-75 in 26.6%. Among patients with between > or = 50 and < 75% PASI improvement at week 12 FT (n = 118), 47.5% improved to PASI-75 with extended treatment. For patients achieving PASI-75 at week 12 FT (n = 164), median time to relapse was 58 days. Re-treatment after relapse led to mean PASI improvement of 62.3% from study baseline (n = 145). Safety results were consistent with previous studies, with no new safety concerns. CONCLUSIONS: These results demonstrate additional benefit of continuing efalizumab. Re-treatment re-established disease control in patients with PASI-75 who relapsed following treatment cessation. The safety profile remained consistent with that seen at 12 weeks.

Administration, Topical↗
PubMed2006

IgA pemphigus--occurrence of anti-desmocollin 1 and anti-desmoglein 1 antibody reactivity in an individual patient.

BACKGROUND: IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti-keratinocyte cell surface antibody reactivity. Two subtypes have been discerned: in the subcorneal pustular dermatosis type, desmocollin 1 has been identified as a targeted autoantigen, while in few cases of the intraepidermal neutrophilic type, IgA anti-desmoglein 1 or IgA anti-desmoglein 3 reactivity has been demonstrated. PATIENTS AND METHODS: A 48-year-old white male presented with generalized large confluent pustules. Skin pathology was assessed by histology and direct immunofluorescence analysis. IgG/IgA autoantibodies against desmoglein 1/3 and desmocollin 1 were measured by ELISA and indirect immunofluorescence using desmocollin 1 cDNA-transfected COS7 cells, respectively. RESULTS: Histopathology revealed subcorneal pustules and direct immunofluorescence microscopy exclusively showed in vivo bound IgA with an intercellular pattern in the epidermis. Desmocollin 1 was identified as a target of IgA autoantibodies by indirect immunofluorescence microscopy utilizing desmocollin 1 cDNA-transfected COS7 cells. In addition, IgA anti-desmoglein 1 reactivity was demonstrated by ELISA. Neither IgA anti-desmoglein 3 nor IgG anti-desmoglein 1/3 autoantibodies were present. CONCLUSIONS: Both desmocollin 1 and desmoglein 1 were autoantigens in this patient with IgA pemphigus and a distinct clinical presentation. To our knowledge, this is the first IgA pemphigus case with dual autoantibody reactivity.

Anti-Bacterial Agents↗
PubMed2005

Dendritic cells in atopic dermatitis: expression of FcepsilonRI on two distinct inflammation-associated subsets.

BACKGROUND: Dendritic cells (DCs) represent a major portion within the infiltrate of atopic dermatitis (AD) lesions. As antigen-presenting cells they have the ability to regulate both the quantity and quality of T-cell responses and, thus, are likely to play a key role in the pathogenesis of T-cell-dominated skin diseases such as AD. Thus we sought to identify the DC repertoire occurring in AD patients. METHODS: For this purpose, we phenotypically analyzed various defined DC subsets of AD patients and healthy controls in skin biopsies and peripheral blood by immunofluorescence staining. RESULTS: In AD lesions, two inflammation-associated DC subsets with varying expression of costimulatory molecules occurred besides epidermal Langerhans cells (LCs) and dermal myeloid DCs (dmDCs) indigenously residing in normal skin: (1) CD1a+/CD1c+/FcepsilonRI+/IgE+/CD207- myeloid DCs (mDCs) in the epidermis and dermis and (2) CD123+/BDCA-2+/CD45RA+/CD68+ plasmacytoid DCs (pDCs) in the dermis. In the peripheral blood of the patients, these cells exhibited an immature phenotype. Interestingly, we found FcepsilonRI and cell-bound IgE to be expressed not only on myeloid, but also on plasmacytoid DCs from both the skin and peripheral blood of AD patients. CONCLUSIONS: It is tempting to speculate that the disease-regulating role of inflammatory DCs in AD is influenced by both FcepsilonRI occupancy and their degree of maturity.

Adult↗
PubMed2005

Hom s 4, an IgE-reactive autoantigen belonging to a new subfamily of calcium-binding proteins, can induce Th cell type 1-mediated autoreactivity.

Skin inflammation in atopic dermatitis starts with Th2 and IgE-mediated responses against exogenous allergens and, for unknown reasons, resembles features of a Th1-driven reaction in the chronic stages. We report the characterization of a human protein, Hom s 4, recognized by IgE autoantibodies from atopic dermatitis patients. The complete Hom s 4 cDNA codes for a 54-kDa basic protein containing two typical calcium-binding domains separated by an unusually long alpha-helical domain. Therefore, Hom s 4 and homologous proteins found by sequence comparison in mice, fruit flies, and nematodes constitute a novel subfamily of calcium-binding proteins. Using Hom s 4-specific Abs, it is demonstrated that the protein is strongly expressed within epidermal keratinocytes and dermal endothelial cells. Purified Hom s 4 showed IgE cross-reactivity with exogenous calcium-binding allergens from plants and fish but, in contrast to the exogenous allergens, induced only weak histamine release from patient basophils. However, the analysis of Hom s 4-specific cytokine and humoral immune responses indicated that Hom s 4 strongly induces Th1 responses which are accompanied by the release of IFN-gamma, a cytokine implicated in epithelial cell damage. Hom s 4-induced IFN-gamma production was found in normal individuals, in patients with chronic inflammatory skin diseases and in Th2-prone atopic persons, suggesting that Hom s 4 represents a protein with an intrinsic property to induce Th1-mediated autoreactivity. It may thus contribute to chronic skin inflammation in atopic as well as in nonatopic persons.

Adult↗
PubMed2005

Balance between NF-kappaB and JNK/AP-1 activity controls dendritic cell life and death.

The life cycle of dendritic cells (DCs) must be precisely regulated for proper functioning of adaptive immunity. However, signaling pathways actively mediating DC death remain enigmatic. Here we describe a novel mechanism of hierarchical transcriptional control of DC life and death. Ligation of tumor necrosis factor receptor superfamily (TNFR-SF) members on DCs and cognate contact with T cells resulted in quantitatively balanced nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)-mediated activator protein-1 (AP-1) induction and strongly enhanced DC longevity. Specific blockade of NF-kappaB in DCs induced strongly augmented JNK/AP-1 activity because of elevated levels of reactive oxygen species. In this scenario, DC activation by TNFR-SF members or T cells induced DC apoptosis. Specific inhibition of JNK/AP-1 rescued DCs from this activation-induced cell death program and restored TNFR-SF member- and T-cell-mediated survival. We conclude that JNK/AP-1 activity is under negative feedback control of NF-kappaB and can execute apoptosis in DCs. Thus, feedback-controlled signaling amplitudes of 2 transcriptional pathways decide the fate of a DC.

CD40 Antigens↗
PubMed2005

CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells.

CCL18 is a human chemokine secreted by monocytes and dendritic cells. The receptor for CCL18 is not yet known and the functions of this chemokine on immune cells are not fully elucidated. In this study, we describe that CCL18 is present in skin biopsies of atopic dermatitis (AD) patients but not in normal or psoriatic skin. CCL18 was specifically expressed by APCs in the dermis and by Langerhans and inflammatory dendritic epidermal cells in the epidermis. In addition, the serum levels of CCL18 and the percentages of CCL18-producing monocyte/macrophages and dendritic cells were significantly increased in AD patients compared with healthy controls. Furthermore, we demonstrate that CCL18 binds to CLA(+) T cells in peripheral blood of AD patients and healthy individuals and induces migration of AD-derived memory T cells in vitro and in human skin-transplanted SCID mice. These findings highlight a unique role of CCL18 in AD and reveal a novel function of this chemokine mediating skin homing of a subpopulation of human memory T cells.

Animals↗
PubMed2005

Atopic dermatitis with increased severity along a line of Blaschko.

Several primarily symmetric skin diseases may, on rare occasions, manifest themselves more prominently along the embryonic migration pathways of cutaneous cell clones. Loss of heterozygosity along these lines of Blaschko resulting in hemizygosity or homozygosity of alleles predisposing for the disease is the most likely explanation for this phenomenon. Here, we report a case of severe Blaschko linear atopic dermatitis superimposed on a milder symmetric eruption of atopic eczema in a 36-year-old man with personal and familial history of allergy. Continuous transition of linear atopic eczema to linear vesicular (dyshidrotic) plantar eczema demonstrates the relationship between these two entities. Individuals such as our patient offer an opportunity to identify intraindividual genetic variations marking loci involved in the pathogenesis of atopy and atopic eczema.

Adult↗
PubMed2005

Pimecrolimus leads to an apoptosis-induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis.

BACKGROUND: Apart from the long-used corticosteroids, topical calcineurin inhibitors (tacrolimus, pimecrolimus) represent novel therapeutic options for the treatment of atopic dermatitis. OBJECTIVE: This study was designed to investigate the pathophysiological target cells and mode of action of pimecrolimus in atopic skin. METHODS: Twenty-two patients were randomly assigned to treatment with pimecrolimus cream 1%, matching vehicle cream, or beta-methasone-17-valerate (BMV) cream 0.1% in a randomized, double-blind, vehicle-controlled, parallel group clinical trial. Treatment was given twice daily for 3 weeks. Cryostat sections of skin biopsies were taken before as well as at selected time points after initiation of therapy. For certain experiments, healthy volunteers were topically treated with the creams described twice a day on 5 consecutive days. Epidermal sheets were prepared from suction blisters. For in vitro experiments, untreated, healthy human skin was obtained from patients undergoing plastic surgery. The effect of pimecrolimus and BMV on Langerhans cells (LCs), inflammatory dendritic epidermal cells, and T cells was investigated by using immunofluorescence and flow-cytometry techniques. RESULTS: While topical BMV treatment depleted LCs in healthy and atopic skin, pimecrolimus did not affect their number. Correlating with the disappearance of inflammatory cells, we observed a depletion of inflammatory dendritic epidermal cells and T cells on pimecrolimus and BMV treatment. Furthermore, we show that pimecrolimus depletes T cells by the induction of apoptosis. CONCLUSION: In summary, our data show that pimecrolimus reduces pathological T cells in atopic dermatitis skin via apoptosis, whereas LCs remain unaffected.

Administration, Topical↗
PubMed2005

EMPACT syndrome.

BACKGROUND: Seizure prophylaxis with phenytoin is a common measure in oncologic patients with brain metastases. In these patients, generalized severe adverse drug reactions such as erythema multiforme (EEM) may occur. However, in a subgroup of patients with brain radiation therapy, EEM-like lesions develop particularly in the radiation field. Most recently, the acronym EMPACT (Erythema Multiforme associated with Phenytoin And Cranial radiation Therapy) was proposed to specifically describe this syndrome. PATIENT/METHOD: Here, we report on EMPACT syndrome in a 46-year-old woman. Therapeutic measures included seizure prophylaxis with phenytoin and total brain radiation therapy of brain metastases from bronchial carcinoma. Three weeks after introduction of phenytoin, the patient presented with EEM-like skin lesions restricted to the original radiation field and facial mucocutaneous involvement. After a few days, the rash spread to the upper part of the body. She was also in poor general condition. RESULTS: The immediate cessation of phenytoin therapy, combined with administration of systemic corticosteroids and high dose immunoglobulins along with intensive local treatment and pain medications, resulted in complete resolution of the skin eruption. Patch testing to phenytoin was positive after 72 hours. CONCLUSION: EMPACT should be classified as an specific entity among the EEM-like drug reactions as it only appears after radiotherapy and seizure prophylaxis with the anticonvulsant phenytoin. We propose including specific type IV-sensitization to phenytoin into the definition of EMPACT.

Adrenal Cortex Hormones↗
PubMed2005

Transglutaminases as diagnostically relevant autoantigens in patients with gluten sensitivity.

BACKGROUND: Patients with gluten sensitivity, i. e. celiac disease and dermatitis herpetiformis have anti-endomysial antibodies recognizing transglutaminases, which are usually detected on appropriate tissue sections. It would be desirable to have available a reliable, tissue-independent serological diagnostic tool. We compared disease-specificity and sensitivity of tTG versus eTG-based detection systems for the diagnosis of anti-endomysial IgA-antibodies. PATIENTS AND METHODS: We examined 204 serum samples in duplicates with commercial human ELISA-kits: 54 healthy blood donors, 20 celiac disease, 29 dermatitis herpetiformis and 101 with other autoimmune dermatoses. RESULTS: The tTG-based ELISA proved to be very disease-specific (100 %) and sensitive for the diagnosis of gluten sensitivity (95 % celiac disease; 96.6 % dermatitis herpetiformis). The eTG-based ELISA was also perfectly specific (100 %), but only 15 % of celiac disease-sera and 44.8 % of dermatitis herpetiformis-sera yielded positive results. CONCLUSIONS: The human tTG-ELISA fulfills all criteria of a screening test and, because of being investigator-independent, inexpensive and highly reproducible, compares favorably with the current diagnostic gold standard (indirect immunofluorescence and biopsy) of celiac disease and dermatitis herpetiformis. The low sensitivity of the eTG-ELISA may have technical reasons, but could theoretically also be linked to disease activity or indicate the existence of an as yet undefined disease subset. Studies are currently under way to address these issues.

Adolescent↗
PubMed2005

Biological false-positive tests comprise a high proportion of Venereal Disease Research Laboratory reactions in an analysis of 300,000 sera.

This retrospective study on syphilis screening at the sexually transmitted infection (STI) unit of a University Department emphasizes the necessity of a treponemal-specific test as the appropriate screening test. The Venereal Disease Research Laboratory (VDRL) test for syphilis screening may, under certain circumstances, yield positive results in patients not infected with Treponema pallidum, a phenomenon referred to as biological false-positive (BFP) VDRL test. The aim of this study was to determine the frequency of BFP tests in a large sample of sera. In this retrospective study, we analysed the results of parallel VDRL and T. pallidum haemagglutination (TPHA) testing of a total of 514,940 blood samples obtained from patients at the Vienna General Hospital between January 1988 and November 1999. Patients' sera with incomplete data on stage and sex and duplicate sera were excluded, leaving 300,000 sera for analysis. The seroprevalence for syphilis was 1.77% (n = 5320), as determined by a positive TPHA test. It was significantly higher in male than in female patients (2.03% versus 1.58%, P<0.001). Of the patients reactive in the TPHA test, 3257 (61.2%) were negative in the VDRL. With regard to reactivity in VDRL testing, 2799 patients (0.92%) of the study population were positive, of whom 736 (26%) were biological false positive. BFP reactivity was found in 0.24% of all patients and was significantly higher in women than in men (0.27% versus 0.20%, P<0.001) and in patients over 60 years of age (0.34%) as compared with those under 60 (0.25%, P<0.001). This proportion might be even higher, as reactivity in the VDRL at 1:0 and 1:2 dilutions without a positive treponemal test was not reported. The subgroup of HIV-positive patients (n = 1415) revealed a 10-fold higher rate of BFP tests (2.1% versus 0.24), an effect being statistically significant. In a low syphilis prevalence population, BFP reactions comprise a high proportion of all VDRL reactors. Therefore, the use of the VDRL as a screening procedure is challenged.

Adolescent↗
PubMed2004

Plasmacytoid dendritic cell recruitment by immobilized CXCR3 ligands.

Plasmacytoid dendritic cells (pDCs) recognize microbes, viruses in particular, and provide unique means of innate defense against them. The mechanism of pDC tissue recruitment remained enigmatic because the ligands of CXCR3, the cardinal chemokine receptor on pDCs, have failed to induce in vitro chemotaxis of pDCs in the absence of additional chemokines. In this study, we demonstrate that CXCR3 is sufficient to induce pDC migration, however, by a migratory mechanism that amalgamates the features of haptotaxis and chemorepulsion. To mediate "haptorepulsion" of pDCs, CXCR3 requires the encounter of its cognate ligands immobilized, optimally by heparan sulfate, in a form of a negative gradient. This is the first report of the absolute requirement of chemokine immobilization and presentation for its in vitro promigratory activity. The paradigmatic example of pDC haptorepulsion described here may represent a new pathophysiologically relevant migratory mechanism potentially used by other cells in response to other chemokines.

Antigen Presentation↗
PubMed2004

Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod.

Among the different subsets of dendritic cells (DC) described in humans and mice, epidermal Langerhans cells and dermal DCs represent the only DC populations resident in normal skin. In this study we describe a population of CD4(+)CD3(-) plasmacytoid DC (pDC)-like cells that accumulate in the dermis and spleens of mice topically treated with imiquimod, a low m.w. immune response modifier with potent antiviral and antitumor activities. These CD4(+)CD3(-) cells coexpress GR-1, B220, MHC class II, and, to a lesser extent, CD11c and display the phenotypic features of pDCs described in lymphoid organs. The accumulation of pDC-like cells after imiquimod treatment was detected not only in normal skin, but also in intradermally induced melanomas. Imiquimod treatment leads either to complete regression or to a significant reduction of the tumors. The number of pDCs correlates well with the clinical response of the tumors to the drug, suggesting that the antitumor effects of imiquimod could be mediated at least in part by the recruitment of pDC-like cells to the skin. Therefore, strategies aimed at activating and directing these cells into neoplastic tissues may be a promising and novel approach for the immunotherapy of various types of cancer.

Aminoquinolines↗