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For most of the past decade, stratospheric ozone loss has been observed during the winter/spring months over Arctic environments. On occasion, losses of up to 40% in Scandinavia and Siberia have been recorded during this time. In Canada, sporadic losses of 10 to 20% or more have been reported. In Alaska, Point Barrow (71.3°N) showed a daily total ozone value for March 1997 about 6% below the previous 10-year average. Again, on 17–18 March 1999, Barrow showed record low ozone values for that location for a March day. Since 1971 there has been a downward trend in stratospheric ozone during March across the Arctic. More recently, the winter of 1999–2000 has shown the largest local ozone losses yet seen in the Arctic with over 60% observed in the altitude range of 18 to 20 km. Integrated total ozone column losses amounted to 20 to 25% less ozone than previously observed [see the following URL from the Third European Stratospheric Experiment on Ozone (THESEO) for more information: http://europa.eu.int/comm/research/envsc/theseo.html].

The dramatic rise in incidence of malignant melanoma experienced by populations both within the United States and throughout the world over the last several decades has been attributed to enhanced exposure to the UV spectrum of sunlight radiation. This hypothesis can now be tested using genetically engineered mouse models predisposed to malignant melanoma. Here we use melanoma-prone transgenic mice inappropriately expressing hepatocyte growth factor/scatter factor (HGF/SF) in the skin as an experimental model system to ascertain the consequences of a chronic regimen of suberythemal UV radiation on melanoma genesis. HGF/SF is a multifunctional regulator capable of stimulating growth, motility, invasiveness, and morphogenetic transformation in cells, including melanocytes, expressing its receptor tyrosine kinase Met. HGF/SF transgenic mice demonstrate ectopic interfollicular localization and accumulation of melanocytes within the truncal dermis, epidermis, and junction and if untreated develop primary cutaneous melanoma with a mean onset age of approximately 21 months. Transgenic mice and their wild-type littermates subjected to UV radiation three times weekly using FS40 sunlamps (60% UVB and 40% UVA), with daily UV doses graded from 2.25 to 6.0 kJ/m2, developed skin tumors with a mean onset age of 26 and 37 weeks, respectively (P0.001, Kaplan-Meier log rank test). However, the repeated doses of suberythemal UV radiation used in this study failed to accelerate melanoma genesis, instead inducing the development of nonmelanoma tumors that included squamous cell carcinomas, squamous papillomas, and sarcomas. The conspicuous absence of melanocytic tumors occurred despite the immunohistochemical detection of a significant stimulation (P0.001) in melanocyte-specific bromodeoxyuridine incorporation in response to only 2 weeks of UV irradiation (total UV dose of 13.5 kJ/m2), resulting in 2.6- and 4.6-fold increases in the number of melanocytes in the dermis and epidermis, respectively. These data indicate that chronic suberythemal UV radiation preferentially favors the development of nonmelanocytic over melanocytic neoplasms in this transgenic animal, consistent with the pathogenesis proposed for sun exposure-associated skin cancer based on retrospective studies in the human population. Our findings suggest that the HGF/SF transgenic mouse will be useful as an experimental model for determining the consequences of exposure to various regimens of UV radiation and for elucidating the mechanisms by which such consequences are realized.

Ultraviolet B (UVB, 290-320 nm) radiation initiates in vivo a dose- and wavelength-dependent down regulation of cell-mediated immunity. An action spectrum for UV-induced immunosuppression indicated that the photoreceptor for this effect is urocanic acid (UCA), which undergoes a trans to cis isomerization in the stratum corneum on UV exposure. An accumulation of evidence has supported this conclusion. However, evidence has also been presented that formation of thymine dimers in DNA is responsible for initiation of UV-induced immunosuppression. Because photobinding of UCA to DNA in vitro forming cyclobutane-type adducts has been shown, we sought to resolve this dilemma by investigating if UCA photobinds to DNA in vivo. The [14C]cis-UCA, [14C]trans-UCA or [3H]8-MOP (8-methoxypsoralen) was applied topically to BALB/c mice that were then irradiated with a dose of UV previously shown to cause systemic suppression of contact hypersensitivity. The DNA was prepared from epidermal cells by phenol extraction immediately after in vivo irradiation and bound radioactivity determined. Although photobinding of [3H]8-MOP was readily demonstrable under these conditions (0.9 nmol/mg DNA), no significant binding of either isomer of UCA to DNA (between 1.2 x 10(-3) and 2.1 x 10(-3) ng/mg DNA) could be detected. Uptake studies in keratinocytes prepared from epidermis of untreated animals indicated that [3H]8-MOP was taken up with a rate constant of 4.2 x 10(-3) pmol/s/mg protein/mumol/L. In contrast, uptake of [14C]cis-UCA was not statistically significant from zero and uptake of [14C]trans-UCA was negligible (0.8 x 10(-3) +/- 0.08 x 10(-3) pmol/s/mg protein/mumol/L). There was no significant difference between uptake of UCA isomers, but uptake of [3H]8-MOP was significantly greater than that of either UCA isomer (P0.01). These studies indicate that the photobinding of UCA to DNA does not play a role in UV-induced immunosuppression.

During the past several years it has become clear that alterations in the expression of microRNA genes contribute to the pathogenesis of most, perhaps all, human malignancies. These alterations can be caused by a variety of mechanisms, including deletions, amplifications or mutations involving microRNA loci, by epigenetic silencing or by dysregulation of transcription factors targeting specific microRNAs. Since malignant cells show dependence on the dysregulated expression of microRNA genes, which in turn control or are controlled by dysregulation of multiple protein coding oncogenes or tumour suppressor genes, these small RNAs provide important opportunities for development of future microRNA based therapies.

The systemic effect of ultraviolet (UV) irradiation on delayed type hypersensitivity (DTH), contact hypersensitivity (CHS) and allograft rejection was investigated in BALB/c mice which had been exposed to a single 1 h treatment with UV radiation (27 kJ/m2) from FS40 sunlamps (60% UVB). After UV irradiation (3-5 days), mice were treated on an unirradiated site with either a subcutaneous injection of allogeneic spleen cells or a topical application of the contact sensitizer oxazolone (OX). The DTH response to allogeneic cells and the CHS response to OX elicited 6 days after immunization were significantly lower in UV-treated mice than in normal mice. Spleen cells from these animals were transferred intravenously into X-irradiated (600R) recipients which were immediately challenged with antigen and the DTH or CHS response elicited was determined 24 h later. Recipients of equal numbers of cells from sensitized and normal animals (6 X 10(6) from each donor) exhibited positive DTH or CHS responses to the antigen used to sensitize the donor. In contrast, recipients of equal numbers of cells from animals sensitized and UV suppressed to the same antigen showed a suppressed DTH or CHS response. This suppression was antigen-specific. Treatment of cells from UV suppressed animals, prior to transfer, with complement and cytotoxic anti-Lyt 2 or anti-Thy 1.2 monoclonal antibodies abrogated the suppressive ability of these cells, in contrast to cytotoxic treatment with anti-L3T4 or anti-Lyt 1 monoclonal antibodies which had no significant effect. The suppressor cells therefore had the phenotype Thy 1.2+, Lyt 2+, L3T4-, Lyt 1-.(ABSTRACT TRUNCATED AT 250 WORDS)

Urocanic acid (UCA, deaminated histidine) is a major ultraviolet-absorbing component of the stratum corneum. On UV irradiation, the naturally occurring trans form converts to the cis isomer. We have previously postulated that UV-induced systemic suppression is initiated by cis-UCA by way of an antigen-presenting cell defect. To test this hypothesis further, we have investigated the antigen-presenting cell (APC) function of splenic dendritic cells (DC). Splenic DC were prepared from mice 7 days after 1 h UV irradiation (27 kJ/m2) or i.v. administration of 50-200 micrograms/mouse of cis- or trans-UCA. Dendritic cells from UV-irradiated or cis-UCA-treated mice had a significantly impaired (APC) ability, assessed by the proliferative response of purified T cells from mice immune to DNP6 OVA to DC pulsed with this antigen. Dendritic cells from mice given trans-UCA had normal APC ability. The number of FcR+ cells was the same in DCs from all four treatment groups, and the number of IAd+ cells and the intensity of IAd expression were not decreased in DCs from UV-irradiated or cis-UCA-treated mice. Mixture of DCs from UV- or cis-UCA-treated mice with DCs from normal mice did not suppress APC activity. Dendritic cells taken 3 days after UV or cis-UCA treatment, in contrast to DC taken 7 days after treatment, had normal APC ability, indicating a time delay in the generation of the APC defect. In contrast, addition of cis-UCA or trans-UCA (66 micrograms/ml) directly to an in vitro proliferation assay had no effect, suggesting that cis-UCA may be activated in vivo. These results support our original hypothesis that cis-UCA has a natural role as a modulator of immune function.

This is a story of a young man who accepted the twin responsibility of Surveyor/Astronomer and Second in Command of the Victorian Exploration Expedition, and in so doing accepted death and the stigma of failure as a leader of the Burke and Wills tragedy.

Ultraviolet radiation has a suppressive effect on the immune system in vivo which appears to be a critical step in ultraviolet carcinogenesis, preventing the immunologic rejection of the highly antigenic UV-induced tumours.

Thoracic duct lymph was drained for 28 days from a patient with disseminated malignant melanoma. Lymphocytes were separated from the lymph by centrifugation, and returned to the patient daily. Biochemical and hematologic parameters were monitored in blood and lymph, and were maintained at satisfactory levels throughout the period. Cell-mediated immunity and specific blocking activity directed against melanoma antigens were examined by the leukocyte adherence inhibition test. Blocking factors in drained lymph fell to undetectable levels after 6 days' thoracic duct drainage, whereas it took 9 days for serum blocking factors to fall to similar levels. Peripheral blood leukocytes demonstrated cell-mediated immunity against melanoma antigens before and throughout the period of drainage, except for the immediate postoperative period. Within 24 hours of closure of the thoracic duct fistula, serum blocking activity had returned, and 17 days later the patient died.

The leukocyte adherence inhibition test was used to monitor tumor-specific cell-mediated immunity in 15 patients who had a variety of malignant tumors and were undergoing chemotherapy alone or in combination with immunotherapy by Corynebacterium parvum. A rapid and prolonged loss of cell-mediated immunity in blood leukocytes was observed after treatment in all but one of the patients studied. Abolition of reactivity was due to the lack of production of the soluble lymphokine-like factor affecting leukocyte adherence to glass. A new phenomenon of adherence stimulation by antigen, also mediated by a soluble factor, was observed after treatment in some patients. A drop in titer or total abrogation of serum blocking factors occurred in six of six patients tested following chemotherapy or immunotherapy. The lowered levels of blocking activity persisted during treatment and, with the possible exception of one patient, were not correlated with clinical benefit.

We previously reported that broad band UV radiation or narrow bands of UV (Hbw 3 nm) of wavelengths 250 to 320 nm cause a systemic suppression of contact hypersensitivity (CHS) in mice, observed when the contact sensitizer is applied to a nonirradiated site. To determine if this effect is associated with UV-induced alterations in epidermal Langerhans cell (LC) numbers and morphology, we performed the following study. LC were identified by ATPase staining of EDTA-separated epidermal sheets. Electron microscope studies confirmed that this method was a satisfactory indicator of the presence of LC; we found no evidence for LC which did not stain for ATPase in either irradiated or unirradiated epidermis. Mice were irradiated on the back with narrow band UV of peak wavelength 270, 290, or 320 nm. The irradiated skin was excised 24 hr later and was stained as described. The number of LC with ATPase staining dendrites and the number of nondendritic LC were enumerated. We found that UV radiation of 270 or 290 nm caused 1) an alteration in LC morphology (loss of dendrites) and 2) a decrease in the total number of epidermal LC. Both effects occurred in a dose-dependent fashion. Previously, these same wavelengths of narrow band UV, but at higher doses, had been shown to cause systemic suppression of CHS. In this study, the doses of 270 or 290 nm UV that resulted in the decreased LC numbers and alterations in LC morphology described above were insufficient to cause systemic suppression of CHS. The converse was found if the irradiating waveband of UV had a peak at 320 nm. A dose of 320 nm UV that caused 50% systemic suppression of CHS had no effect on either the number or the morphology of LC at the site of irradiation. In addition, the number and morphology of LC were unaffected in the ventral epidermis (site of contact sensitization) of mice that had been previously irradiated on the back with a systemically suppressive dose of UV. We conclude: (a) UV-induced alterations in the number and morphology of LC at the site of irradiation are not necessary for the generation of systemic suppression of CHS by UV radiation; this indicates that the initial UV-absorbing event triggering systemic suppression is neither a loss of, nor morphologic alterations to, LC at the irradiation site. (b) A systemic effect of UV radiation on the number and morphology of LC at the unirradiated site of contact sensitization does not occur, and thus is not responsible for the UV-induced systemic suppression of CHS by UV radiation.

Contact hypersensitivity to dinitrochlorobenzene (DNCB), picryl chloride (PCl) or oxazolone was induced in mice by skin painting with these agents, and was measured by skin testing in vivo using the ear swelling method. Prior administration of dinitrobenzene sulfonate (DNBS) or picryl sulfonic acid prevented sensitization to DNCB and PCl, respectively. Both this tolerization and the original sensitization were specific for the hapten used. Cyclophosphamide given before sensitization enhanced skin reactions, but when given before tolerization it interfered with establishment of tolerance. Cells from both sensitized and tolerized mice were shown to be reactive with the corresponding haptens in vitro in the leukocyte adherence inhibition (LAI) reaction. LAI specificity was similar to that found for cutaneous reactivity. The reaction of DNCB-sensitized cells with DNBS led to the production of a soluble mediator which induced LAI in normal cells. The demonstration of potentially reactive cells in mice judged to be tolerant by skin testing indicates the concomitant existence of suppressor factors.