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Abstract. The E48 antigen, a putative human homologue of the 20-kD protein present in desmosomal preparations of bovine muzzle, and formerly called desmoglein III (dg4), is a promising target antigen for antibody-based therapy of squamous cell carcinoma in man. To anticipate the effect of high antibody dose treatment, and to evaluate the possible biological involvement of the antigen in carcinogenesis, we set out to molecularly characterize the antigen. A cDNA clone encoding the E48 antigen was isolated by expression cloning in COS cells. Sequence analysis revealed that the clone contained an open reading frame of 128 amino acids, encoding a core protein of 13,286 kD. Database searching showed that the E48 antigen has a high level of sequence similarity with the mouse ThB antigen, a member of the Ly-6 antigen family. Phosphatidylinositol-specific (PI-specific) phospholipase-C treatment indicated that the E48 antigen is glycosylphosphatidylinositol-anchored (GPI-anchored) to the plasma membrane. The gene encoding the E48 antigen is a single copy gene, located on human chromosome 8 in the 8q24-qter region. The expression of the gene is confined to keratinocytes and squamous tumor cells. The putative mouse homologue, the ThB antigen, originally identified as an antigen on cells of the lymphocyte lineage, was shown to be highly expressed in squamous mouse epithelia. Moreover, the ThB expression level is in keratinocytes, in contrast to that in lymphocytes, not mouse strain related. Transfection of mouse SV40-polyoma transformed mouse NIH/3T3 cells with the E48 cDNA confirmed that the antigen is likely to be involved in cell-cell adhesion.

Exposure to ultraviolet light, especially UVB wavelengths, can impair immune responses in animals and humans. It is remarkable that this immunomodulation is not restricted to the exposed skin but is also found at other sites, i.e. systemic (distant) immunosuppression. A frequently proposed hypothesis is that UVB exposure inhibits, specifically, T helper 1 (Th1)-mediated immune responses. The major reason for this is that contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH), both Th1-mediated immune responses, are very sensitive to UVB. For this reason these models are frequently used for photoimmunology studies. In the present study, the effects of UVB exposure were investigated in classical models for Th1-mediated immunity, i.e. CHS models in which picrylchloride or oxazolone were used as low-molecular-weight chemical antigens. In these models, CHS responsiveness and cytokines were measured, the latter by both reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The CHS responses to both contact sensitizers (picrylchloride and oxazolone) were suppressed significantly by pre-exposure to repeated suberythemal UVB exposure. Interferon-gamma (IFN-gamma), interleukin (IL)-12 and IL-4, but not IL-10, were detectable in spleen and draining lymph nodes of sensitized BALB/c mice. Repeated UVB exposure prior to sensitization at a distant locus inhibited both IFN-gamma and IL-12 but not IL-4. In BALB/c mice sensitized with ovalbumin (OVA) in the absence of complete Freund's adjuvant, a model for Th2-mediated immunity, OVA-specific serum IgE and cytokine profiles in the spleen were analysed. Sensitization did lead to a significant increase in OVA-specific IgE serum titres. Pre-exposure to UVB resulted in a decreased OVA-specific IgE serum titre. Both RT-PCR and ELISA showed increased levels of IFN-gamma, IL-4 and IL-10 in the spleens of OVA-sensitized mice. The production of IFN-gamma and IL-4 was not affected by UVB pre-exposure. In contrast, the production of IL-10 was significantly increased. This was probably caused by an up-regulation of Th2 cells. It is remarkable that IFN-gamma is significantly suppressed by UVB in Th1-mediated immune reactions but not in Th2-mediated immune reactions where it even appears to increase. IL-10, which is up-regulated by UVB pre-exposure and produced by, among others, Th2 cells, may represent a shift from Th1- to Th2-mediated immune mechanisms. However, IL-10 can also inhibit Th2 responses, which might be the reason for a decreased IgE titre in the Th2 model. From the results of this study it is concluded that UVB exposure prior to sensitization/immunization not only inhibits Th1-mediated but also Th2-mediated immune responses.

Background. In animal models, HMG-CoA reductase inhibitors were able to improve renal function and endothelium-dependent vascular reactivity. In various experimental renal diseases, including autosomal dominant polycystic kidney disease (ADPKD), HMG-CoA reductase inhibitors improved the rate of decline in renal function. We studied the effect of simvastatin on ADPKD patients. Methods. In a double-blind cross-over study, 10 normocholesterolaemic ADPKD patients were treated in random order for 4 weeks with 40 mg simvastatin or placebo daily. After each treatment period, we investigated the effect of simvastatin on renal blood flow and endothelium-dependent vascular reactivity. These periods were separated by a 4-week wash-out period. Results. After treatment with simvastatin, glomerular filtration rate (GFR) significantly increased from 124"4 mlumin to 132"6 mlumin (P-0.05). Simultaneously, effective renal plasma flow (ERPF) increased significantly from 494"30 mlumin to 619"67 mlumin after simvastatin treatment (P-0.05). These renal effects were accompanied by a significantly enhanced vasodilator response to acetylcholine in the forearm after simvastatin treatment. Total serum cholesterol levels were significantly reduced after treatment with simvastatin, from 4.24"0.32 to 3.17"0.22 mmolul (P-0.001). Conclusion. We concluded that simvastatin treatment can ameliorate renal function in ADPKD patients, by increasing renal plasma flow, possibly via improvement of endothelial function. Long-term clinical trials with HMG-CoA reductase inhibitors are needed to confirm these results and to establish a chronic inhibiting effect of HMG-CoA reductase inhibitors on the progression towards end-stage renal disease in ADPKD patients.