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Biomedical subjects

T Schwarz

Publications and source records attributed to T Schwarz.

At least 91 records · Page 5Linked to original sources
PubMed2000

Expression of proopiomelanocortin peptides in human dermal microvascular endothelial cells: evidence for a regulation by ultraviolet light and interleukin-1.

Proopiomelanocortin peptides such as alpha-melanocyte-stimulating hormone and adrenocorticotropin are expressed in the epidermal and dermal compartment of the skin after noxious stimuli and are recognized as modulators of immune and inflammatory reactions. Human dermal microvascular endothelial cells mediate leukocyte-endothelial interactions during cutaneous inflammation by the expression of cellular adhesion molecules and cytokines such as interleukin-1. This study addresses the hypothesis that human dermal microvascular endothelial cells express both proopiomelanocortin and prohormone convertases, which are required to generate proopiomelanocortin peptides. Semiquantitative reverse transcriptase polymerase chain reaction and northern blot studies revealed a constitutive expression of proopiomelanocortin mRNA by human dermal microvascular endothelial cells in vitro that was time- and concentration-dependently upregulated by interleukin-1 beta. Furthermore, irradiation of human dermal microvascular endothelial cells with ultraviolet A1 (30J per cm(2)) or ultraviolet B (12.5 mJ per cm(2)) enhanced proopiomelanocortin expression as well as the production and release of the proopiomelanocortin peptides adrenocorticotropin and alpha-melanocyte-stimulating hormone. In addition to proopiomelanocortin, prohormone convertase 1 mRNA expression was detected by reverse transcriptase polymerase chain reaction in unstimulated human dermal microvascular endothelial cells and was augmented after exposure to alpha-melanocyte- stimulating hormone, interleukin-1 beta, or irradiation with ultraviolet. These findings demonstrate that human dermal microvascular endothelial cells express proopiomelanocortin and prohormone convertase 1 required for the generation of adrenocorticotropin. Additionally, human dermal microvascular endothelial cells express mRNA for the prohormone convertase 2 binding protein 7B2. Taken together these findings indicate that human dermal microvascular endothelial cells upon stimulation express both proopiomelanocortin and prohormone convertases required for the generation of alpha-melanocyte-stimulating hormone. As proopiomelanocortin peptides were found to regulate the production of human dermal microvascular endothelial cell cytokines and adhesion molecules and to have a variety of anti-inflammatory properties these peptides may significantly contribute to the modulation of skin inflammation. J Invest Dermatol 115:1021-1028 2000

Adrenocorticotropic Hormone↗
PubMed2000

Detection of ventricular fibrillation in implantable defibrillators with automatic gain control amplifiers: effects of programming sensitivity.

AIMS: In newer implantable cardioverter-defibrillators with automatic gain control amplifiers the maximum possible sensitivity is programmed with the aim of securing optimal detection of ventricular fibrillation. This study was designed to prove that a reduction in maximum sensitivity is safe with respect to appropriate sensing of ventricular fibrillation, while avoiding sensing of extracardiac signals. METHODS AND RESULTS: Forty-two consecutive patients, undergoing defibrillator implantation/replacement with programmable maximum auto-gain sensing sensitivity (Ventak Mini III, Ventak AV , Guidant, St. Paul, MN, U.S.A.), were prospectively investigated. Thirty-four patients were implanted with a dual-coil lead system, providing integrated bipolar sensing (Endotak, Guidant, St. Paul, MN, U.S.A.), eight patients received a single-coil lead system with true bipolar sensing (Sprint, Medtronic, Minneapolis, MN, U.S.A.). During device implantation and pre-discharge testing, arrhythmia detection times of induced ventricular fibrillation were compared at programmed maximum (0.18 mV) and minimum (0.43 mV) sensitivity in a randomized manner. Seventy-six induced episodes of ventricular fibrillation were analysed. The mean arrhythmia detection times did not differ between the programmed sensing levels (maximum sensitivity: 1612 +/- 307 ms, vs minimal sensitivity: 1,602 +/- 330 ms; P = ns). The results were not affected by the type of implanted lead system (integrated bipolar versus true bipolar sensing). CONCLUSION: In the implantable defibrillator devices, reduction in maximum sensitivity did not impair the detection of induced episodes of ventricular fibrillation.

Amplifiers, Electronic↗
PubMed2000

Method-dependent influence of certain polymorphisms in the factor V B-domain on the response to activated protein C.

The factor V (FV) B-domain is extremely important to the cofactor function of native FV for activated protein C (APC) in the inactivation of factor VIII (FVIII). In a previous study, we found that in the B-domain coding portion of DNA, the polymorphisms at nucleotide positions 2391, 2663, 2684, and 2863 were associated. In the major allele, all bases are A (A allele) and those in the minor allele are G (G allele). This study concerns itself with the question of whether or not there are differences in the APC response between the A allele and the G allele in plasma samples from persons without the FV Leiden. The APC ratios of homozygous carriers of the major A allele and the minor G allele do not differentiate themselves in classical activated partial thromboplastin time-based assays. In contrast, a test based on the deactivation of FVIII in the tenase complex in homozygous carriers of the minor G allele showed significantly lower APC ratios (P = 0.001) in comparison with the major A allele. The results of the investigation after modification of the test indicate that mutative changes in the B-domain apparently influence the interaction among phospholipids, APC, FV, and protein S. An increase in FVIII through the introduction of the FVIII concentrate Kogenate to the plasma samples was associated with a drop in the APC ratios of both genotypes. After defining 59 age- and sex-based matched pairs without the FV Leiden, the observed frequency of the minor G allele was higher in the non-thrombotic group (33.0%) than in the thrombotic group (22.8%). However, the difference did not reach the level of significance (odds ratio, 0.53; 95% confidence interval, 0.26-1.12). It does, nevertheless, appear possible that a homozygous condition for the minor allele in combination with a defect known to be associated with thrombophilia represents an additional thrombogenetic risk factor.

Activated Protein C Resistance↗
PubMed2000

Osteopenia and other radiographic signs in canine hyperadrenocorticism.

The specificity of conventional radiography in assessing canine hyperadrenocorticism was evaluated by comparing the Incidence of related radiographic findings in 24 hyperadrenocorticoid, 15 diabetic and 20 hypothyroid dogs. Hyperadrenocorticoid dogs showed significantly more perihilar bronchial mineralisation than other groups. There was no significant variation between the disease groups with respect to obesity, hepatomegaly, contour of the caudoventral hepatic margin, peripheral bronchial mineralisation or osteopenia. Adrenal mineralisation and calcinosis cutis were rare findings observed only in hyperadrenocorticoid dogs. The effect of obesity on the radiographic appearance of bone was studied using a dissected lumbar spine from a canine cadaver. An osteopenic effect could be demonstrated by superimposition of a 10 cm-thick fat block. The low specificity of almost all common signs in canine hyperadrenocorticism and the low incidence of characteristic findings demonstrate the limited potential of radiography in assessing this condition. Radiographic assessment of bone density is unreliable because of artefactual osteopenic effects of high kVp settings necessary in obese dogs.

Adrenocortical Hyperfunction↗
PubMed1999

Reduced ultraviolet-induced carcinogenesis in mice with a functional disruption in B7-mediated costimulation.

Immunosuppression by UV light contributes significantly to the induction of skin cancer by suppressing the cell-mediated immune responses which control the development of carcinogenesis. The B7/CD28-CTLA-4 signaling pathway provides costimulatory signals essential for Ag-specific T cell activation. To investigate the role of this pathway in photocarcinogenesis, we utilized transgenic (Tg) mice which constitutively express CTLA-4Ig, a high-affinity CD28/CTLA-4 antagonist that binds to both B7-1 and B7-2. The transgene is driven by a skin-specific promoter yielding high levels of CTLA-4Ig in the skin and serum. Chronic UV exposure of CTLA-4Ig Tg mice resulted in significantly reduced numbers of skin tumors, when compared to control mice. In addition, Tg mice were resistant to UV-induced suppression of delayed-type hypersensitivity responses to alloantigens. Most importantly, upon stimulation with mitogens and alloantigens, T cells isolated from CTLA-4Ig Tg mice produced significantly less IL-4 but more IFN-gamma compared to control T cells, suggesting an impaired Th2 response and a relative increase of Th1-type immunity. Together, these data show that overall B7 engagement directs immune responses toward the Th2 pathway. Moreover, they point out the crucial role of Th1 immune reactions in the protection against photocarcinogenesis.

Abatacept↗
PubMed1999

Role of epidermal cell-derived alpha-melanocyte stimulating hormone in ultraviolet light mediated local immunosuppression.

Irradiation of the skin with ultraviolet light (UV) results in profound alterations of both local and systemic immune responses. These effects are largely mediated by soluble mediators released from epidermal cells in response to UV. It is well known that keratinocytes release increased amounts of cytokines upon UV-irradiation. UV-light also induces the release of the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha MSH), from keratinocytes, and upregulates the expression of POMC mRNA. alpha MSH exerts a variety of immunomodulating and antiinflammatory effects, mainly by virtue of its capacity to alter the function of antigen presenting cells and vascular endothelial cells. Within an in vivo mouse-model, both intravenous and topical application of alpha MSH resulted in inhibiting the induction, eliciting a contact hypersensitivity reaction, and inducing hapten-specific tolerance. These findings indicate that alpha MSH, released in the epidermis after UV irradiation, may contribute to UV-mediated immunosuppression. The therapeutic application of alpha MSH or alpha MSH-derived peptides may prove to be a useful approach for treating inflammatory skin diseases.

Animals↗
PubMed1999

Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand- and CD95-induced apoptosis but not from ultraviolet radiation-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a new member of the tumor necrosis factor (TNF) family, induces apoptosis primarily of transformed cells. Interleukin-1 was previously found to protect the keratinocyte cell line KB from TRAIL-induced apoptosis, thus we studied whether interleukin-1 also protects from other apoptotic stimuli (ultraviolet radiation (UV), CD95-ligand). Interleukin-1 rescued KB cells from TRAIL- and CD95-induced apoptosis, which was critically dependent on nuclear factor kappaB, because cells transfected with a super-repressor form of the nuclear factor kappaB inhibitor IkappaB were less protected. In contrast, UV-mediated apoptosis was not only not prevented by interleukin-1 but even enhanced. This opposite effect of interleukin-1 was also observed for the expression of the inhibitor of apoptosis proteins (IAP). Whereas TRAIL- and CD95-mediated suppression of IAP expression was partially reversed by interleukin-1, UV-mediated down-regulation of IAPs was not reversed but even further enhanced. Increased apoptosis induced by interleukin-1 plus UV was accompanied by excessive TNFalpha release, implying that enhanced cytotoxicity is due to the additive effect of these two apoptotic stimuli. Accordingly, enhanced apoptosis was reduced by blocking the TNF receptor-1. The opposite effects of interleukin-1 indicate that different mechanisms are involved in UV-induced apoptosis compared with CD95- and TRAIL-mediated apoptosis. Furthermore, the data suggest that whether a signal acts in an antiapoptotic way or not does not only depend on the signal itself but also on the stimulus causing apoptosis.

Apoptosis↗
PubMed1999

Nickel allergy in mice: enhanced sensitization capacity of nickel at higher oxidation states.

Attempts to induce contact hypersensitivity to nickel in mice using, e.g., Ni(II)Cl2 often failed. Here, we report that sensitization was achieved by injecting Ni(II)Cl2 in combination with either CFA or an irritant, such as SDS and PMA, or IL-12, or by administering nickel at higher oxidation states, i.e., Ni(III) and Ni(IV). Although Ni(II), given alone, was ineffective in T cell priming, it sufficed for eliciting recall responses in vivo and in vitro, suggesting that Ni(II) is able to provide an effective signal 1 for T cell activation, but is unable to provide an adequate signal 2 for priming. Immunization of mice with nickel-binding proteins pretreated with Ni(IV), but not with Ni(II), allowed them to generate nickel-specific CD4+ T cell hybridomas. Ni(II) sufficed for restimulation of T cell hybridomas; in this and other aspects as well, the hybridomas resembled the nickel-specific human T cell clones reported in the literature. Interestingly, restimulation of hybridomas did not require the original Ni(IV)-protein complex used for priming, suggesting either that the nickel ions underwent ligand exchange toward unknown self proteins or peptides or that nickel recognition by the TCR is carrier-independent. In conclusion, we found that Ni(III) and Ni(IV), but not Ni(II) alone, were able to sensitize naive T cells. Since both Ni(III) and Ni(IV) can be generated from Ni(II) by reactive oxygen species, released during inflammation, our findings might explain why in humans nickel contact dermatitis develops much more readily in irritated than in normal skin.

Animals↗
PubMed1999

Nuclear and cell membrane effects contribute independently to the induction of apoptosis in human cells exposed to UVB radiation.

UVB-induced DNA damage is a crucial event in UVB-mediated apoptosis. On the other hand, UVB directly activates death receptors on the cell surface including CD95, implying that UVB-induced apoptosis can be initiated at the cell membrane through death receptor clustering. This study was performed to measure the relative contribution of nuclear and membrane effects in UVB-induced apoptosis of the human epithelial cell line HeLa. UVB-mediated DNA damage can be reduced by treating cells with liposomes containing the repair enzyme photolyase followed by exposure to photoreactivating light. Addition of photolyase followed by photoreactivation after UVB reduced the apoptosis rate significantly, whereas empty liposomes had no effect. Likewise, photoreactivating treatment did not affect apoptosis induced by the ligand of CD95, CD95L. UVB exposure at 4 degrees C, which prevents CD95 clustering, also reduced the apoptosis rate, but to a lesser extent. When cells were exposed to UVB at 4 degrees C and treated with photolyase plus photoreactivating light, UVB-induced apoptosis was almost completely prevented. Inhibition of caspase-3, a downstream protease in the CD95 signaling pathway, blocked both CD95L and UVB-induced apoptosis, whereas blockage of caspase-8, the most proximal caspase, inhibited CD95L-mediated apoptosis completely, but UVB-induced apoptosis only partially. Although according to these data nuclear effects seem to be slightly more effective in mediating UVB-induced apoptosis than membrane events, both are necessary for the complete apoptotic response. Thus, this study shows that nuclear and membrane effects are not mutually exclusive and that both components contribute independently to a complete response to UVB.

Antigens, CD↗
PubMed1999

Transfection of immature murine bone marrow-derived dendritic cells with the granulocyte-macrophage colony-stimulating factor gene potently enhances their in vivo antigen-presenting capacity.

Ag presentation by dendritic cells (DC) is crucial for induction of primary T cell-mediated immune responses in vivo. Because DC culture from blood or bone marrow-derived progenitors is now clinically applicable, this study investigated the effectiveness of in vitro-generated murine bone marrow-derived DC (Bm-DC) for in vivo immunization protocols. Previous studies demonstrated that GM-CSF is an essential growth and differentiation factor for DC in culture and that in vivo administration of GM-CSF augments primary immune responses, which renders GM-CSF an attractive candidate to further enhance the effectiveness of DC-based immunotherapy protocols. Therefore, immature Bm-DC were transiently transfected with the GM-CSF gene and tested for differentiation, migration, and Ag-presenting capacity in vitro and in vivo. In vitro, GM-CSF gene-transfected Bm-DC were largely unaltered with regard to MHC and costimulatory molecule expression as well as alloantigen or peptide Ag-presenting capacity. When used for in vivo immunizations, however, the Ag-presenting capacity of GM-CSF gene-transfected Bm-DC was greatly enhanced compared with mock-transfected or untransfected cells, as determined by their effectiveness to induce primary immune reactions against hapten, protein Ag, and tumor Ag, respectively. Increased effectiveness in vivo correlated with the better migratory capacity of GM-CSF gene-transfected Bm-DC. These results show that GM-CSF gene transfection significantly enhances the capacity of DC to induce primary immune responses in vivo, which might also improve DC-based vaccines currently under clinical investigation.

Adjuvants, Immunologic↗
PubMed1999

Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage.

Bone marrow-derived dendritic cells (BmDC) are potent APC and can promote antitumor immunity in mice when pulsed with tumor Ag. This study aimed to define the culture conditions and maturation stages of BmDC that enable them to optimally function as APC in vivo. BmDC cultured under various conditions (granulocyte-macrophage CSF (GM-CSF) or GM-CSF plus IL-4 alone or in combination with Flt3 ligand, TNF-alpha, LPS, or CD40 ligand (CD40L)) were analyzed morphologically, phenotypically, and functionally and were tested for their ability to promote prophylactic and/or therapeutic antitumor immunity. Each of the culture conditions generated typical BmDC. Whereas cells cultured in GM-CSF alone were functionally immature, cells incubated with CD40L or LPS were mature BmDC, as evident by morphology, capacity to internalize Ag, migration into regional lymph nodes, IL-12 secretion, and alloantigen or peptide Ag presentation in vitro. The remaining cultures exhibited intermediate dendritic cell maturation. The in vivo Ag-presenting capacity of BmDC was compared with respect to induction of both protective tumor immunity and immunotherapy of established tumors, using the poorly immunogenic squamous cell carcinoma, KLN205. In correspondence to their maturation stage, BmDC cultured in the presence of CD40L exhibited the most potent immunostimulatory effects. In general, although not entirely, the capacity of BmDC to induce an antitumor immune response in vivo correlated to their degree of maturation. The present data support the clinical use of mature, rather than immature, tumor Ag-pulsed dendritic cells as cancer vaccines and identifies CD40L as a potent stimulus to enhance their in vivo Ag-presenting capacity.

Animals↗