Notizen: Summary In the past decade, there has been enormous progress in the understanding of the pathomechanisms of immune-mediated diseases, which has led to major advances in immunotherapeutic strategies. As a consequence, the armamentarium of specific and nonspecific immune-modulating and immunosuppressive drugs for the treatment of skin diseases has been widely extended. Among the nonspecific immunomodulators, mycophenolate mofetil and leflunomide show promising effects in a variety of autoimmune and inflammatory skin disorders. Both compounds inhibit a key enzyme in nucleotide biosynthesis, a step that is pivotal for the production of cytotoxic T cells and antibody formation. They do not act in the nucleus, which may explain their advantageous side-effect profile.

Notizen:   Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated.

Notizen: We investigated transcutaneous partial CO2 and O2 pressures and respiratory rate in unpremedicated elderly patients of ASA physical status 1 to 3 who underwent cataract surgery under retrobulbar anaesthesia. In group A no air suction was used. In group B suction was applied under the sterile drapes to avoid rebreathing of CO2. In group A transcutaneous partial CO2 pressure and respiratory rate significantly increased compared with baseline, whereas in group B they remained constant. In both groups transcutaneous partial O2 pressure and oxygen saturation as measured by pulse oximetry significantly rose after insufflating oxygen 3 lmin−1. Heart rate and mean arterial blood pressure remained constant. Our results demonstrate that the application of suction near the patient's head prevents CO2 rebreathing and subsequent hypercapnia associated with an elevated respiratory rate. The use of suction makes it unnecessary to raise oxygen administration. Suction combined with monitoring of partial CO2 pressure using transcutaneous sensors should be used in all ophthalmological operations under retrobulbar anaesthesia.

Notizen: The epidermis has been identified as an important site for the initiation of immunological events. In addition to the macrophage-like Langerhans cells, keratinocytes within the epidermal cells have been shown to act as immunoregulatory cells through the secretion of cytokines such as epidermal cell-derived thymocyte-activating factor (ETAF) and interleukin 3. Epidermal cell-derived interleukin 3 (EC IL-3), like lymphocyte-derived IL-3, induced the proliferation of IL-3-dependent mast cell-like cell lines. Biochemically, EC IL-3 was a heat-stable protein with a molecular weight of approximately 30 kD. Upon chromatofocusing, EC IL-3 exhibited three isoelectric points, at pI 7.8, 7.4, and 7.1. Furthermore, an antiserum against IL-3 neutralized EC IL-3 activity, suggesting that the molecules are closely related and share similar epitopes. ETAF-like macrophage-derived interleukin 1 (IL-1) is a low molecular weight protein with a multiplicity of amplifying effects on immunological and inflammatory reactions. Thus BALB/c mice were immunized with partially purified IL-1, and immune spleen cells were hybridized with plasmocytoma cells. Supernatants of the hybridoma cultures were screened for their capacity to inhibit IL-1-induced thymocyte proliferation. After expansion and cloning, one clone was selected for ascitic antibody production. The monoclonal anti-IL-1 antibody inhibited both the IL-1-dependent thymocyte and the fibroblast proliferation. Furthermore, the antibody blocked murine and human ETAF activity, suggesting that ETAF and IL-1 share antigenically similar domains. Moreover, by using the monoclonal antibody bound to Staphylococcus aureus cells, it was possible to immunoprecipitate IL-1. In contrast, anti-IL-1 antibody did not inhibit IL-2 or IL-3 activity. These findings demonstrate that the production of immunoregulatory cytokines is not confined to cells of the immune system and that keratinocytes through the production of ETAF and EC IL-3 may mediate inflammatory and hypersensitivity reactions. Furthermore, the monoclonal anti-IL-1 antibody may provide a useful tool for the development of new immunoassays to detect IL-1/ETAF and thereby facilitate the investigation of the role of these cytokines during the pathogenesis of inflammatory diseases.

Notizen: Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) belong to the same superfamily of neuropeptides which exert their effects by activating G-protein-coupled receptors defined as PACAP. So far, three receptor subtypes exist (PAC1R, VPACR-1 and VPACR-2). Because, PACAP appears to play a crucial role in cutaneous inflammation and vasoregulation, we examined the expression and biological effects of this peptide in primary human dermal microvascular endothelial cells (HDMECs). We detected the expression of PACAP and VPAC type 1 receptor at RNA and protein level by RT-PCR and immunohistochemistry, indicating an autocrine regulatory mechanism. cAMP assays revealed VPAC1R to be functional in these cells. RT-PCR showed upregulation of IL-8 in a time- and dose-dependent manner. ELISA experiments confirmed release of IL-8 by HDMEC cells. We also investigated cell adhesion molecule expression after stimulation with PACAP. ICAM-1 mRNA was upregulated at 3 and 6 h after treatment with PACAP, while VCAM was only upregulated maximally at 6 h after PACAP stimulation, indicating the regulation of cell adhesion molecule expression in human dermal endothelial cells via VPAC1R. Immunoreactivity for VPAC-1R was enhanced in microvascular endothelial cells of patients with atopic dermatitis and urticaria, indicating upregulation of this receptor in endothelial cells during cutaneous inflammation. In summary, VIP and PACAP may play an important role in cutaneous neurogenic inflammation by activating VPAC-1R on dermal microvascular endothelial cells.

Notizen: Dermal microvascular endothelial cells (ECs) are both source and target of the pro-opiomelanocortin (POMC) peptides ACTH and α-melanocyte-stimulating hormone (α-MSH). The availability of neuropeptides as important modulators of innate and adaptive immune responses is controlled by neuropeptide-specific peptidases such as neutral endopeptidase (NEP) or angiotensin-converting enzyme (ACE). In this study, we have tested the possibility that NEP or ACE expressed by ECs may influence the local bioavailability of POMC peptides. Incubation of ACTH1−39 with cell membranes prepared from the high NEP-/low ACE-expressing microvascular EC line 1 (HMEC-1) or from low NEP-/high ACE-expressing primary human dermal ECs (HDMECs) for 30–480 min resulted in a decrease in ACTH immunoreactivity (IR) over time in membrane supernatants that could be partially blocked with NEP inhibitors as detected by radioimmunoassay. In parallel, α-MSH IR increased peaking after 60 min. Fragments generated by incubation of HMEC-1 or HDMEC membranes with ACTH1−39, ACHT1−24 or α-MSH for 1–120 min were further analysed by mass spectroscopy. HMEC-1 membranes generated peptide products which could be altered by inhibition of NEP, but not ACE. Likewise, HDMEC membranes fragmented ACTH similar to HMEC-1 membranes in the presence of NEP inhibitors. Some of the proteins can be assigned to regular proteolytic cleavage, while others seem to be modified. Importantly, HMEC-1 and HDMEC membranes also slowly degraded α-MSH, suggesting that EC proteolytic peptidases locally control ACTH/α-MSH bioavailability, which may be important in controlling cutaneous inflammation.

Notizen: Summary Tacalcitol is a vitamin D analogue which has been developed for the therapy of psoriasis vulgaris. The treatment with a twice daily application of 2μg/g ointment is efficacious and safe in Japanese patients. The objective of this randomized, placebo-controlled, intraindividual right-left comparison was to investigate the efficacy and safety of 8 weeks' therapy with a once daily application of a 4 μg/g tacalcitol ointment in Caucasian psoriatics.The data on 122 male and female patients were analysed. The score sum of erythema, infiltration and desquamation was influenced significantly more by tacalcitol ointment than by placebo (P〈0.0001) at every control point, starting from week 2. With regard to the individual symptoms of desquamation, infiltration and erythema, the treatment with tacalcitol was also superior to placebo treatment beginning at week 2. Qualitatively, the same results were obtained with the preference assessment of both treated body sides and also the global assessments of efficacy and benefit. Symptoms of local skin irritation which may be related to the active compound or the ointment base were reported by 12·3% of patients. In only one patient, irritation required discontinuation of tacalcitol treatment. Laboratory criteria, including serum calcium, serum phosphate and serum levels of calcitonin, parathormone, 1α,24-dihydroxyvitamin D3 and 25- hydroxyvitamin D3 did not reveal any changes of clinical relevance during or after treatment. Furthermore, the global assessment of tolerance was good or very good in more than 90% of cases. The results of this study demonstrate that the once daily application of a 4 μg/g tacalcitol ointment is an efficacious therapy for psoriasis vulgaris in Caucasian patients, and that its tolerance is good, wherever the lesion is located, including on the face.

Notizen: Long-term treatment with interferon alpha (IFN-α) has recently been shown to reduce the bone marrow infiltrate and cutaneous lesions in systemic mast cell disease. We therefore administered this cytokine to six patients with urticaria pigmentosa for up to 12 months, using subcutaneous injections of 5×106U, initially five times, and subsequently three times a week. The generally well-tolerated therapy resulted in marked improvement of the cutaneous symptoms, especially in three of the patients who suffered from very severe pruritus. Two of the patients with bone marrow infiltration showed normal findings after treatment. However, in none of the patients was there any change in the skin lesions, or decrease in the degree of cutaneous mast cell infiltration, as evidenced by light and electron microscopic examination. These findings indicate that IFN-α is highly effective in the control of symptoms, but otherwise does not influence the cutaneous lesions of urticaria pigmentosa.