| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
Ultraviolet A-1 (340-400 nm) radiation is highly effective in inducing apoptosis in skin-infiltrating T-cells and thereby exerts beneficial effects in patients with T-cell-mediated skin diseases such as atopic dermatitis and cutaneous T-cell lymphoma (UVA-1 phototherapy). In the in-vitro study we report that malignant and normal T-cells differ in their susceptibility towards UVA-1 radiation-induced apoptosis. Dose-response studies revealed that malignant CD4+ T-cells isolated from a patient with adult T cell leukemia or from a patient with Sezary's syndrome as well as cells from different, malignant T cell lines (HUT 102,ATL102,HPB-ALL, Jurkat, MOLT4) exhibited a significantly higher susceptibility towards UVA-1 radiation-induced apoptosis 4 hours (early apoptosis) and 24 hours (late apoptosis) after exposure than normal, nonmalignant CD4+ T-cells (5 different donors ; p<0.05). This difference was specific for UVA-1 irradiation because it was not detected when apoptosis was induced in
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these cells through exposure to UVB radiation or stimulation with exogenously added, cell permeable ceramides. In previous studies it has been shown that UVA-1 radiation-induced T-cell apoptosis is initiated through the generation of singlet oxygen and subsequently mediated through the FAS/FASL system. This is in agreement with the present observation that stimulation of unirradiated cells with a singlet oxygen generating system induced apoptosis in malignant cells to a greater extent than in nonmalignant, normal cells, and this difference was similar to that observed after UVA-1 irradiation. Moreover, downregulation of FAS surface expression in malignant T cells (Jurkat) through repetitive stimulation with FAS antibody or FASL transfectant was associated with the inhibition of UVA-1 radiation/singlet oxygen-induced apoptosis in these cells. It is well known that FAS-induced apoptosis is mediated further downstream by caspases. It was thus of great interest to learn that addition of the caspase inhibitor Z-VADfmk decreased and interferon-γ stimulation, which is known to upregulate caspase levels including caspase-3,increased the sensitivity of T-cells towards UVA-1 radiation-induced apoptosis. Moreover, malignant T-cells had significantly higher procaspase 3 levels when compared with normal cells. These studies indicate that the susceptibility of human T-cells towards UVA-1 radiation-induced apoptosis is related to the availability of caspases such as caspase 3 and that strategies directed at upregulating caspase levels may increase the efficacy of UVA-1 phototherapy. Less
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