Neue Entwicklungen in der systemischen Psoriasistherapie

The current standard systemic therapeutic modalities for psoriasis have many potential side effects. Progress made in the understanding of the pathophysiology of psoriasis as a T‐cell‐mediated dermatosis provide options for new more precise therapeutic approaches. These immunological therapeutic strategies involve the inhibition/depletion of activated T‐lymphocytes, the inhibition of antigen presentation and thus the regulation of T‐cell activation, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory mediators and the administration of antiinflammatory cytokines. This article summarizes these new systemic therapeutic approaches. Clinical results in the early studies have been mixed. In the next years further results of phase II‐ and phase III‐studies may be expected, which should allow better assessment of the potential of those particular approaches. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options. Furthermore results of therapeutic experiments should contribute to a better understanding of the disease. As we learn which mechanisms are more or less important for the disease, we will be better able to plan intervention strategies.     

Fluid shear induced endothelial cell detachment from glass - influence of adhesion time and shear stress

In this study, human umbilical vein and human saphenous vein endothelial cells were seeded on glass and exposed to fluid shear in a parallel-plate flow chamber. Cell retention, morphology and migration were studied as a function of shear stress and of adhesion time prior to exposure to shear. Three-hour and 24-h adhesion times gave rise to comparable cell retention values after 2 h of flow for both cell types. Cell retention decreased from 85 to 20% as shear stress increased from 88 to 264 dynes cm⁻² (8.8 to 26 Pa). Mean spreading areas decreased after the onset of flow, but subsequently stabilized to plateau values, which were smaller at higher shear stresses. Shape factors increased faster to higher values as cells were exposed to higher shear stresses, without any obvious preference in orientation of the cells with respect to the direction of flow. Migration was unidirectional with flow and linear with time. Migration was faster for cells which had adhered for 24 h than for cells which had adhered for 3 h and was accompanied by the presence of fibrillar structures left behind on the surface upstream of migrating cells. It is concluded that after 3 h adhesion to glass, cells have adhered with an adhesion strength that does not substantially increase during the next 21 h. However, during this time changes in cell-substratum interactions seem to occur judging by the differences in, e.g., migration rates.     

Natural killer cell activity and CSF monoamine metabolites in suicide attempters

The aim of this study was to investigate markers of serotonin and immune function in suicidal patients. Cytotoxic activity of natural killer cells (NK) and CD16 lymphocytes were studied in 28 suicide attempters and 26 healthy controls, and related in patients to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF). Patients with CSF 5-HIAA below the median had significantly lower NK cell activity than other patients. CD16 cell frequency was significantly lower in patients than in controls, and patients also tended to have lower NK cell cytotoxicity than healthy controls. There were no statistically significant correlations between 4-hydroxy-3methoxyphenyl glycol (HMPG), homovanillic acid (HVA), CSF cortisol and NK cell activity. The results support the hypothesis of compromised immune function in suicidal patients with evidence of disordered serotonin function.     

Antimutagenic activities of naturally occurring polyamines in Chinese hamster ovary cells in vitro

Spermine and spermidine, ubiquitous polyamines present in bacteria and animal cells, are also involved in cell growth. Since they interact with the double helix, they can stabilize the DNA molecule. Recent evidence of the antimutagenic and anticarcinogenic capacity of spermine has focused attention on the mechanism(s) by which such agents can protect cells from induced damages. In the present paper we show the ability of spermine and spermidine to decrease the level of sister chromatid exchanges induced in Chinese hamster ovary cells cultivated in vitro, by treating them with Psoralen + UVA irradiation (able to induce mainly monoadducts and DNA cross-links). Two different mechanisms of polyamine action can be invoked to explain the preservative activity of this class of agents.     

亮氨酸脑啡肽对脂多糖促血管平滑肌细胞增殖效应的抑制作用

观察亮氨酸脑啡肽和脂多糖对血平滑肌细胞增殖的影响，并观察两者之间的相互作用及阿片受体阻滞剂纳洛酮的影响，方法：实验以离体培养的ＳＤ大鼠胸主动脉ＶＳＭＣ为模型。     

Use of commercially available cell culture inserts for primary culture and electrophysiologic studies of guinea pig gastric mucous epithelial cells

Summary The adherence, growth, and electrophysiologic properties of guinea pig gastric mucous epithelial cells were investigated using porous membrane filters. We also tested three commercially available Ussing-type chambers that were designed to be used with the various porous membrane supports. Overall, the 0.45-µm Falcon-Cyclopore porous membrane was found to be very favorable for the consistent attachment and growth of our cells. This same filter also gave good results in the detection of periodic acid Schiff-positive mucous glycoprotein and Nile red neutral lipid fluorescence in the gastric mucous cells. Our cells grew poorly on collagen-coated Costar-Snapwells and Millipore Millicell-CM porous filters. For measurement of transepithelial potential difference resistance, and short-circuit current, the Costar-Snapwell with the Costar-Snapwell Diffusion-chamber system was superior in design and operation when compared to the Costar Transwell-COL, Falcon-Cyclopore, or Anotec-Anocell porous inserts used with conventional Ussing-chambers. The gastric mucous cells grew best on ICN-Cellagen membranes, but these filters routinely detached from their plastic holder and therefore could not be used for Ussing-chamber studies. The large 24.5-mm, 0.40-µm pore size Costar-Transwell-COL and the 24.1-mm, 0.45-µm Falcon-Cyclopore membranes gave good results when used in a modified horizontal-chamber for microelectrode analysis of membrane potentials and resistances of the gastric mucous cell monolayers.     

Ventrally emigrating neural tube cells migrate into the developing vestibulocochlear nerve and otic vesicle

Virtually all cell types in the inner ear develop from the cells of the otic vesicle. The otic vesicle is formed by the invagination of non-neural ectodermal cells known as the otic placode. We investigated whether a recently described cell population, originating from the ventral part of the hindbrain neural tube known as the ventrally emigrating neural tube (VENT) cells, also contributes cells to the otic vesicle. The ventral hindbrain neural tube cells were labeled with the fluorescent vital dye DiI or replication-deficient retroviruses containing the LacZ gene in chick embryos on embryonic day 2, after the emigration of neural crest from this region. One day later, the labeled cells were detected only in the hindbrain neural tube. Shortly thereafter, the labeled cells began to appear in the eighth (vestibulocochlear) cranial nerve and otic vesicle. From embryonic day 3.5-5, the labeled cells were detected in the major derivatives of the otic vesicle, i.e. the endolymphatic duct, semicircular canals, utricle, saccule, cochlea, and vestibulocochlear ganglion. That the emigrated cells originated from the ventral part of the hindbrain neural tube was confirmed by focal application of DiI impregnated filter paper and with quail chimeras. It is concluded that, in addition to the otic placode cells, the otic vesicle also contains the ventrally emigrating neural tube cells, and that both cell populations contribute to the structures and cell types in the inner ear. It is well known that inductive signals from the hindbrain are required for the morphogenesis of the inner ear. The migration of the hindbrain neural tube cells into the otic vesicle raises the possibility that the inductive effect of the hindbrain might be mediated, at least in part, by the ventrally emigrating neural tube cells and that, therefore, a mechanism exists that involves cells rather than diffusible molecules only.     

Induction of type II collagen-specific antibody production in blood lymphocyte cultures of rhesus monkeys (Macaca mulatta) with collagen-induced arthritis using the immobilized native antigen.

Peripheral blood mononuclear cells (PBMC) from Rhesus monkeys previously immunized with bovine type II collagen to induce arthritis were cultured with the same antigen. Because the native protein is poorly soluble in culture medium a heating step is often used. The antigen in this form induced PBMC proliferation, but epitopes for the induction of antibody production and arthritis were lost. To keep the native protein intact it was coated on affigel beads. With the immobilized antigen specific antibody production could be induced.     

Differential effects of luminol,nickel, and arsenite on the rejoining of ultraviolet light and alkylation-induced DNA breaks

When Chinese hamster ovary cells were treated with ultraviolet (UV) light or methyl methanesulfonate (MMS), a large number of DNA strand breaks could be detected by alkaline elution. These strand breaks gradually disappeared if the treated cells were allowed to recover in a drug-free medium. The presence of nickel or arsenite during the recovery incubation retarded the disappearance of UV-induced strand breaks, whereas the disappearance of MMS-induced strand breaks was retarded by the presence of arsenite or of luminol, a new inhibitor for poly(ADP-ribose) synthetase. Luminol, however, had no apparent effect on the repair of UV-induced DNA strand breaks, and nickel had no effect on the repair of MMS-induced DNA strand breaks. When UV- or MMS-treated cells were incubated in cytosine arabinofuranoside (AraC) plus hydroxyurea (HU), a large amount of low molecular weight DNA was detected by alkaline sucrose sedimentation. The molecular weight of these DNAs increased if the cells were further incubated in a drug-free medium. This rejoining of breaks in cells pretreated with UV plus AraC and HU was inhibited by nickel and by arsenite, but not by luminol. The rejoining of breaks in cells pretreated with MMS plus AraC and HU was inhibited by luminol and by arsenite, but not by nickel. These results suggest that different enzymes may be used in DNA resynthesis and/or ligation during the repairing of UV- and MMS-induced DNA strand breaks, and that nickel, luminol, and arsenite may have differential inhibitory effects on these enzymes. © 1994 Wiley-Liss, Inc.     

Immunohistochemical characterization of cellular infiltrates in squamous cell carcinoma and Bowen's disease occurring in one patient.

We investigated populations of the infiltrating cells in Bowen's disease (BD) and squamous cell carcinoma (SCC), both of which arose in the same patient, using the Avidin-Biotin-peroxidase complex method with eight monoclonal antibodies. T lymphocytes were most predominant among infiltrating cells; NK cells, B cells, and monocytes were rarely seen in either BD or SCC. Analysis of subsets of the infiltrating T lymphocytes revealed that the number of suppressor/cytotoxic (s/c) T cells was twice that of helper/inducer (h/i) T cells in BD, while the number of s/c T cells was lower than that of h/i T cells in SCC. The immunohistochemical results in the present case differed from those of predominant infiltration of h/i T cells and of s/c T cells in three other reports of BD and SCC. These results suggest that the population of the cellular infiltrates may be modulated by the nature of tumors and by the immuno-competent state of the hosts.