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C Neumann

Publications and source records attributed to C Neumann.

At least 19 recordsLinked to original sources
PubMed1999

Enhancement of human IL-4 activity by soluble IL-4 receptors in vitro.

The recombinant form of the extracellular domain of the IL-4 receptor (sIL-4R) is a potential candidate to neutralize IL-4; however, murine sIL-4R displayed both antagonistic and agonistic activity in vivo. Here we show that human recombinant sIL-4R induced the formation of complexed IL-4 in supernatants of activated T cells in a dose-dependent manner as measured by newly developed enzyme-linked immunosorbent assays. These IL-4/sIL-4R complexes liberated free IL-4 even after prolonged culturing. In contrast, in the absence of exogenously added sIL-4R, free IL-4 was rapidly consumed or proteolytically degraded in cultures of activated T cells. Thus, no IL-4 bioactivity could be determined in supernatants of T cells activated in the presence of IL-4 for 6 days. In contrast, the same cultures carried out in the presence of sIL-4R showed marked IL-4 bioactivity. While low concentrations of sIL-4R enhanced IL-4-driven inhibiton of IFN-gamma production by activated T cells, higher concentrations neutralized IL-4. Together, human sIL-4R, besides its activity as an antagonist to IL-4, also possesses protective and agonistic functions for IL-4, which may be relevant for clinical studies aiming to neutralize IL-4 in vivo.

Animals↗
PubMed1999

A radiation hybrid map of the zebrafish genome.

Recent large-scale mutagenesis screens have made the zebrafish the first vertebrate organism to allow a forward genetic approach to the discovery of developmental control genes. Mutations can be cloned positionally, or placed on a simple sequence length polymorphism (SSLP) map to match them with mapped candidate genes and expressed sequence tags (ESTs). To facilitate the mapping of candidate genes and to increase the density of markers available for positional cloning, we have created a radiation hybrid (RH) map of the zebrafish genome. This technique is based on somatic cell hybrid lines produced by fusion of lethally irradiated cells of the species of interest with a rodent cell line. Random fragments of the donor chromosomes are integrated into recipient chromosomes or retained as separate minichromosomes. The radiation-induced breakpoints can be used for mapping in a manner analogous to genetic mapping, but at higher resolution and without a need for polymorphism. Genome-wide maps exist for the human, based on three RH panels of different resolutions, as well as for the dog, rat and mouse. For our map of the zebrafish genome, we used an existing RH panel and 1,451 sequence tagged site (STS) markers, including SSLPs, cloned candidate genes and ESTs. Of these, 1,275 (87.9%) have significant linkage to at least one other marker. The fraction of ESTs with significant linkage, which can be used as an estimate of map coverage, is 81.9%. We found the average marker retention frequency to be 18.4%. One cR3000 is equivalent to 61 kb, resulting in a potential resolution of approximately 350 kb.

Animals↗
PubMed1999

Erosive mucosal lichen planus: response to topical treatment with tacrolimus.

Erosive mucosal lichen planus is a painful and disabling inflammatory skin disease that is highly resistant to topical treatment. We report on six patients with severe recalcitrant erosive mucosal lichen planus who benefited from topical application of tacrolimus ointment. After 4 weeks of treatment, complete resolution was observed in three cases, and substantial improvement was achieved in the other three patients. In these cases, prolonged treatment resulted either in further improvement or in complete healing. All patients reported rapid relief from pain and burning. No severe side-effects were observed.

Administration, Topical↗
PubMed1999

IFN-gamma is only partially restored by co-stimulation with IL-12, IL-2, IL-15, IL-18 or engagement of CD28.

BACKGROUND: Although it is well established that T cells derived from patients with atopic diseases produce low levels of interferon-gamma (IFN-gamma), the mechanisms responsible for this phenomenon are poorly understood. OBJECTIVES: To elucidate whether IFN-gamma production may be restored by co-stimulatory molecules known to increase IFN-gamma production in vitro. Further, to investigate whether deficient IFN-gamma production is associated with disease activity. METHODS: Purified peripheral T cells obtained from patients with severe atopic dermatitis (AD), individuals with a history but no symptoms of AD and healthy control subjects were activated with anti-CD3 MoAbs in the presence or absence of anti-CD28 MoAbs, interleukin (IL-) 12, IL-2, IL-15 or IL-18. IFN-gamma production was determined at the single cell level by flow cytometry, as well as by ELISA. RESULTS: Activated T cells from patients with severe AD produced less IFN-gamma than T cells from healthy control individuals. IL-12 or engagement of CD28 enhanced IFN-gamma production in both healthy and atopic T cells. However, absolute values of IFN-gamma were still different. IL-2, IL-15 and IL-18 did not restore IFN-gamma production. T cells from individuals with a history of AD produced more IFN-gamma than those from subjects with severe AD, but less than T cells from healthy individuals. Atopic T cells expressed regular levels of CD3, CD28 and Stat4, the main signal transducer and activator of transcription for IL-12. IL-4, IL-10 and TGF-beta production by T cells were not different between healthy and atopic individuals. CONCLUSION: IFN-gamma deficiency in atopic T cells is not due to a lack of responsiveness to CD28, IL-12, IL-2, IL-15 or IL-18. T cell-derived cytokines able to antagonize IFN-gamma do not contribute to decreased IFN-gamma production. The extent of IFN-gamma deficiency seems to be dependent on disease activity.

Adolescent↗
PubMed1999

Inverse correlation of domestic exposure to Dermatophagoides pteronyssinus antigen patch test reactivity in patients with atopic dermatitis.

BACKGROUND: In recent years considerable interest in the pathogenetic role of aeroallergens exacerbating atopic dermatitis (AD) has emerged. The 'atopy patch test' with aeroallergens was introduced by Platts-Mills et al. as an experimental model and as a diagnostic tool. However, its relevance for the clinical manifestation of AD is still not clear. OBJECTIVE: We asked whether there is a relationship between the individual antigen exposure to the major allergen of Dermatophagoides pteronyssinus (Der p 1) and the immunological markers of sensitization to Der p 1 or the clinical severity of AD. METHODS: We investigated 92 patients with moderate to severe AD. For clinical evaluation the SCORAD severity score was used. Patch tests were performed with purified Der p 1. Specific IgE was measured by a commercial assay. Der p 1 exposure was quantified in a sample of the patient's mattress dust by using a commercial ELISA. RESULTS: No correlation between SCORAD, Der p 1 exposure and RAST could be established. However, there was an unexpected significant inverse correlation between the quantity of mite antigen in the mattress dust and patch test reactivity. Patients with a high antigen load (> 25 microg/g) mostly had a negative patch test. Also, when Der p 1 was correlated to the mattress area (m2) in this group all patch tests were negative. A possible explanation could be that continuous exposure of the skin to house dust mite allergen Der p 1 may induce a down-regulation of the skin immune system of patients with AD. CONCLUSION: Although the mechanism of this phenomenon is presently unknown, our study shows that a positive allergen patch test alone should not be an indication to undertake allergen exclusion measures in AD patients.

Adolescent↗
PubMed1999

Mechanisms of deficient interferon-gamma production in atopic diseases.

BACKGROUND: The mechanisms responsible for an imbalanced cytokine response in atopic diseases are still not understood. While impaired interferon-gamma (IFN-gamma) production may be the result of a pathological T-cell/antigen-presenting cell (APC) interaction, evidence was provided that the T cell itself may have an intrinsic defect to produce IFN-gamma. OBJECTIVE: To clarify whether impaired IFN-gamma production by T cells from patients with atopic dermatitis (AD) represents an intrinsic defect in producing IFN-gamma. METHODS: Effector T cells were generated from CD4+ CD45RA+-naive precursors from patients with AD and healthy control individuals by activation with anti-CD3+ anti-CD28 MoAbs. Following restimulation, IFN-gamma production was measured by ELISA and flow cytometry. RESULTS: IFN-gamma production by atopic T cells was decreased compared with healthy T cells. IL-12 present at priming or high doses of IL-2 during the culture period, even in the absence of IL-12, completely restored IFN-gamma production. Conversion of naive CD45RA+ to CD45R0+ effector cells did not differ between atopic and healthy donors' T cells. CONCLUSION: Impaired IFN-gamma production by T cells from atopic individuals is not the result of an intrinsic, genetically fixed, defect to produce sufficient amounts of IFN-gamma. The data provides evidence that correction of an impaired TH1 response in AD may be successful at the precursor T cell level.

Adolescent↗
PubMed1999

Combined analysis of polymorphisms of the tumor necrosis factor-alpha and interleukin-10 promoter regions and polymorphic xenobiotic metabolizing enzymes in psoriasis.

Environmental and genetic factors are thought to interact in the manifestation of psoriasis, but knowledge about the involved genes and antigens is incomplete. This study has focused on the association between psoriasis and inherited variations in xenobiotic metabolism and cytokine production as two components that may influence cutaneous immune responses to foreign substances. Polymorphisms of N-acetyltransferase 2, glutathione S-transferases T1 and M1, and promoter polymorphisms of the genes encoding for tumor necrosis factor-alpha and interleukin-10 were investigated in 151 Caucasian patients with psoriasis (100 with type I and 51 with type II psoriasis) and in 123 healthy controls. Polymorphisms were detected by polymerase chain reaction-based methods, restriction enzyme analysis, and direct sequencing. There were no significant differences in the distribution of enzyme polymorphisms or point mutations at position -1082 of the interleukin-10 promoter between the psoriasis groups and the control group. The G-->A polymorphism at position -238 of the tumor necrosis factor-alpha promoter (TNF alpha-238*A allele) was more common in type I psoriasis (27%) than in the controls [9.8%; odds ratio 3.4 (95% confidence interval 1.6-7.2); p = 0.0012; pcorr = 0.018]. Surprisingly, this overrepresentation of the tumor necrosis factor alpha-238*A allele was observed in male patients [4.1 (1.5-11.0); p = 0.0046; pcorr = 0.064] but not in female patients [1.8 (0.5-6.5); p = 0.5]. The G-->A polymorphism at position -308 of the tumor necrosis factor-alpha promoter was less frequent in type I psoriasis (23%) compared with controls (35.7%), although the negative association was weak [0.54 (0.3-0.97); p = 0.041; pcorr = not significant]. The distribution of the TNF alpha-238*A and TNF alpha-238*A alleles was similar in type II patients and controls. Our results suggest that male carriers of the G-->A polymorphism at position -238 of the tumor necrosis factor-alpha promoter are at an increased risk to develop early-onset psoriasis.

Adolescent↗
PubMed1999

Soluble human interleukin-4 receptor is produced by activated T cells under the control of metalloproteinases.

BACKGROUND: Soluble interleukin 4 receptors (sIL-4R) are present in biological fluids. In contrast to mice, in man no distinct mRNA coding for sIL-4R has been described, suggesting that human sIL-4R is exclusively produced by proteolytic cleavage of the cell surface receptor. It is not known whether human sIL-4R is actively produced during an immune response. METHODS: Human purified T cells, CD4+, CD8+, CD45RA+ and CD45R0+ T cell subpopulations were activated in vitro. sIL-4R was determined in the supernatants, cell surface IL-4R was measured by flow cytometry and RT-PCR. RESULTS: Recombinant sIL-4R inhibited IL-4-mediated proliferation and IL-5 upregulation by T cells. sIL-4R could be detected at low levels in supernatants of nonactivated T cells, but at high levels following TCR engagement. This response was paralleled by enhanced transcription and de novo synthesis of the human cell surface IL-4R. Both, activated naive CD45RA+ and memory CD45R0+ T cells, produced sIL-4R with long-lasting kinetics. IL-4 increased sIL-4R production by activated CD45RA+, but there was less of an increase by CD45R0+ T cells. In addition, interferon-gamma enhanced sIL-4R production. Cycloheximide and dexamethasone inhibited sIL-4R production by activated T cells, but did not abolish constitutive release of sIL-4R. Phosphoramidon and 1,10-phenanthroline dose-dependently inhibited shedding of the IL-4R, even in nonactivated T cells. CONCLUSION: The production of human sIL-4R by T cells is regulated by TCR stimuli, IL-4 and IFN-gamma and needs the activity of metalloproteinases. Thus, sIL-4R should be regarded as inducible and due to its IL-4-antagonizing activity an immunoregulatory molecule.

Animals↗
PubMed1998

Detection of and discrimination between total and free human interleukin-4 and free soluble interleukin-4 receptor by ELISA.

Interleukin-4 (IL-4) signaling is initiated by binding of IL-4 to the high-affinity IL-4 receptor alpha-chain and subsequent interaction with the common gamma-chain. Soluble forms of the extracellular domain of the alpha-chain (sIL-4R) were shown to be present in biological fluids and, dependent on the concentration, enhance or inhibit IL-4 activity by forming IL-4/sIL-4R complexes. To discriminate between free and potentially active IL-4 from the inactive and complexed form, we have established a set of new ELISA systems for the measurement of human IL-4 in its distinct forms. To select suitable pairs of anti-IL-4 antibodies, a chequerboard interference analysis with six highly-selective human IL-4 specific monoclonal antibodies was performed. For the determination of total IL-4, a monoclonal capture antibody was used that binds IL-4 outside the binding site of the IL-4R alpha-chain. Another antibody recognizing an epitope of the alpha-chain binding site was chosen for the detection of free IL-4. The binding of this antibody was inhibited in a dose-dependent fashion by recombinant sIL-4R. Assays for both total and free IL-4 exhibited a sensitivity of 8 pg/ml and a dynamic range up to 1000 pg/ml. Human sIL-4R was detected by two monoclonal antibodies directed against different epitopes. This ELISA was inhibited by recombinant IL-4 suggesting the measurement of predominantly free sIL-4R. Complexes between soluble IL-4R and IL-4 were detected by a monoclonal anti-sIL-4R antibody in combination with an anti-IL-4 antibody. When supernatants of activated T cells were analyzed, the majority of the IL-4 was in free form. The amount of complexed IL-4 was low as indicated by the fact that most of total IL-4 could be detected as free IL-4. Although values obtained for complexed IL-4 correlated with the difference between total and free IL-4, precise values could not be determined, presumably due to the dynamic nature of the complex between the two proteins. We suggest that the ability to quantitate total and free IL-4 in combination with sIL-4R may provide a new insight of the role that IL-4 plays in different pathophysiological conditions.

Antibodies, Monoclonal↗
PubMed1998

[Granuloma eosinophilicum faciei--successful cryosurgery treatment of 6 patients].

Six patients with granuloma faciale, including patients with multiple lesions, were treated successfully with cryosurgery. Granuloma faciale is known to be difficult to treat. Cryosurgery is an effective and minimally invasive therapy for this granulomatous inflammation of the skin. It should be considered as an alternative to dapsone.

Adult↗
PubMed1998

[Sclerosing in multiple familial glomangiomas].

Glomus tumors (glomangiomata) are benign tumors arising from glomus cells. Multiple glomangiomata are less frequent and less painful than the solitary variant, which is usually located subungually. Nonetheless multiple glomangiomata--sometimes being sensitive to pressure and changes in temperature--may cause considerable discomfort. Treatment of multiple glomangiomata is problematic because of the often large number of tumors. Sclerotherapy represents an alternative to surgical and cryosurgical therapy. We report on sclerotherapy in a 35 year old female patient with multiple hereditary glomus tumors.

Adult↗
PubMed1998

[Erythrokeratodermia progressiva symmetrica Darier-Gottron with generalized expression].

A mother and her son presented with erythrokeratodermia progressiva symmetrica Darier-Gottron. Both patients developed symmetrical erythematous and hyperkeratotic plaques on the extremities and face at the age of 6 months. At the age of 2 1/2 years the son suffered from rapid progression of the disease to involve the entire skin. The disease of his mother had shown a similar course, however, with spontaneous regression at the age of 10 years. The clinical features of this generalized condition were identical to congenital lamellar ichthyosis. Light microscopy was non-specific with orthohyperkeratosis, focal parakeratosis and acanthosis. Electron microscopy revealed numerous keratinosomes in the stratum granulosum, keratinosome-derived lamellae in the intercellular space and partly augmented keratohyalin with clumping. In the stratum spinosum short tonofilament bundles with clumping were remarkable. The child experienced a significant and persistent improvement with systemic retinoids. His mother's disease was successfully controlled with intermittent retinoid therapy. With the clinical and ultrastructural criteria presently available, an unambiguous differentiation between erythrokeratodermia progressiva symmetrica, usually a localized disorder of keratinization, however with intermittent generalization, and other disorders of keratinization seems difficult.

Adult↗
PubMed1998

[Pediatric polytrauma. A retrospective comparison between pediatric, adolescent and adult polytrauma].

Numerous epidemiological studies about multiple trauma patients do not include an analysis of patients under the age of 18. To study this, the data of 682 patients with multiple traumata, treated between 1981 and 1991 at Hannover Medical School, Germany, were retrospectively analyzed. The patients were divided into four age-related groups: preschool age (< 6 years), school age (< 13 years), teenagers (< 18 years) and adults (> or = 18 years). Analyzed were the cause of trauma, localization of injuries and the cause of death. Children were less often injured as passengers in cars, but more often injured as pedestrians and bicyclists than adults. However, children showed a significant higher mortality than adults, with threefold increased risk of death when they injured as passengers in car accidents. In all groups injuries to the head and the legs were most common. Children showed a lower incidence of trauma to the thorax, abdomen, hip and arms than the adult group. Nevertheless, trauma to the thorax, abdomen and head was associated with the highest risk of death in all groups. Spinal cord injuries, especially injuries to the neck, also showed a high risk of death. Children younger than 6 years had the most severe head injuries. Safety improvements for children in cars, helmet usage on bicycles and early training in traffic safety for children might decrease the lethality in this group of trauma patients.

Adolescent↗
PubMed1998

Specific autologous anti-melanoma T cell response in vitro using monocyte-derived dendritic cells.

Dendritic cells (DC) are antigen-presenting cells initiating primary and secondary immune responses. Since malignant tumors are able to escape immunologic control, DC might be prime candidates to activate the immune system against tumor cells. In an autologous system, a dynamic interaction among monocyte-derived DC (MoDC), T lymphocytes, and tumor cells obtained from melanoma patients could be noted. MoDC were generated from blood monocytes in the presence of GM-CSF, IL-4, and IFN-gamma. T cells were isolated either from peripheral blood or from lymph nodes. Melanoma cells were harvested from surgically removed tumor metastases. They were then gamma-irradiated and co-cultured with autologous MoDC and T lymphocytes. After 5 days, the lymphocytes showed a high proliferative activity and the majority of them were CD8-positive. In five cases tested, they revealed a high cytotoxic activity resulting in apoptosis of tumor cells. These findings suggest that MoDC are capable of initiating an effective specific anti-tumor response in a strictly autologous mixed lymphocyte tumor culture (MLTC), even though tumor-specific antigens had not been individually defined. Therefore (I) whole melanoma cells can serve as a source of antigen, (II) monocyte-derived dendritic cells may process and present melanoma-specific antigens resulting in a strong lymphocyte proliferation, (III) the majority of responding T lymphocytes are CD8-positive, and (IV) an acquired cytotoxic response eventually leads to apoptosis of the melanoma cells. The reaction demonstrated here permits to in vitro and quantitatively monitoring the effect of T cell directed immunotherapies such as the adoptive immunotherapy of tumors.

Cell Differentiation↗
PubMed1998

Epidermal cytokines IL-1beta, TNF-alpha, and IL-12 in patients with atopic dermatitis: response to application of house dust mite antigens.

Epidermal cytokines such as interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-12 have been described to play a crucial role in the induction and elicitation phase of allergic contact dermatitis upon exposure to haptens. In this study we asked whether these cytokines may also play a role in the epidermis of patients with atopic dermatitis after the application of house dust mite antigens (HDM) to their skin. Epidermal samples were collected by scraping healthy appearing skin of atopic patients and healthy individuals 8 h after the application of an extract of HDM. Sodium lauryl sulfate and saline served as controls. Reverse transcriptase-polymerase chain reaction was performed for IL-1beta, tumor necrosis factor-alpha, IL-12 p35, and IL-12 p40. Exposure to HDM led to a significant upregulation of mRNA of these cytokines in atopic patients only. Whereas IL-1beta and tumor necrosis factor-alpha also showed an upregulation in part of these patients after exposure to the irritant sodium lauryl sulfate, IL-12 p40 mRNA was exclusively enhanced by the application of the allergen. In contrast to IL-12 p40, IL-12 p35 mRNA was not detectable in significant amounts. Interestingly, also in untreated, normal appearing skin of atopic individuals (n = 16), the levels of these cytokines were higher than in normal individuals (n = 8), possibly explaining the increased skin irritability of atopic individuals. Finally, comparing epidermal cytokines in the skin of patients who developed a positive allergen patch test to those who stayed negative, suggests that only expression of IL-1beta mRNA may be a predictive marker for the development of a positive patch test reaction to HDM.

Animals↗