THE PHOTOBIOLOGICAL ANALYSIS AND THE CLINICAL APPLICATION OF UVA1

UVA1的光生物学分析及临床应用

• 批准号: 14570818
• 负责人: MORITA Akimichi
• 金额: $ 2.3万
• 依托单位: NAGOYA CITY UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570818/
• 关键词: ULTRAVIOLET RADIATION; PHOTOTHERAPY; SKIN DISEASE; T CELL; APOPTOSIS; FAS; LYMPHOMA; SINGLET OXYGEN

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 … More 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

紫外线A-1（340-400 nm）辐射在诱导皮肤浸润性T细胞的凋亡方面非常有效，从而在患有T细胞介导的皮肤疾病如特应性皮炎和皮肤T细胞淋巴瘤（UVA-1光疗）的患者中发挥有益作用。在体外研究中，我们报告说，恶性和正常的T细胞不同，他们对UVA-1辐射诱导的细胞凋亡的敏感性。剂量反应研究表明，从成人T细胞白血病患者或塞扎里综合征患者中分离出的恶性CD 4 + T细胞以及来自不同恶性T细胞系的细胞（HUT 102，ATL 102，HPB-ALL，Jurkat，MOLT 4）对UVA-1辐射诱导的细胞凋亡表现出显著更高的敏感性，暴露后24小时（早期凋亡）和24小时（晚期凋亡）的CD 4 + T细胞比正常的非恶性CD 4 + T细胞的凋亡率高（5个不同的供体; p<0.05）。这种差异对于UVA-1辐射是特异性的，因为当在小鼠中诱导凋亡时没有检测到这种差异。 ...更多信息 这些细胞通过暴露于UVB辐射或用外源性添加的细胞可渗透的神经酰胺刺激而生长。在先前的研究中，已经表明UVA-1辐射诱导的T细胞凋亡是通过单线态氧的产生开始的，随后通过FAS/FASL系统介导。这与目前的观察结果一致，即用单线态氧产生系统刺激未照射的细胞，在恶性细胞中比在非恶性的正常细胞中诱导更大程度的凋亡，并且这种差异与UVA-1照射后观察到的差异相似。此外，通过FAS抗体或FASL转染子的重复刺激，恶性T细胞（Jurkat）中FAS表面表达的下调与UVA-1辐射/单线态氧诱导的细胞凋亡的抑制有关。众所周知，FAS诱导的细胞凋亡在下游由半胱天冬酶介导。因此，非常感兴趣的是，了解到添加半胱天冬酶抑制剂Z-VAD抑制剂降低了T细胞对UVA-1辐射诱导的细胞凋亡的敏感性，并且已知干扰素-γ刺激上调半胱天冬酶水平，包括半胱天冬酶-3，增加了T细胞对UVA-1辐射诱导的细胞凋亡的敏感性。此外，与正常细胞相比，恶性T细胞具有显著更高的半胱天冬酶原3水平。这些研究表明，人类T细胞对UVA-1辐射诱导的细胞凋亡的易感性与半胱天冬酶如半胱天冬酶3的可用性有关，并且针对上调半胱天冬酶水平的策略可以增加UVA-1光疗的功效。少

项目成果

Akira Takashima: "Allergic Contact Dermatitis"Landes Bioscience(印刷中). (2004)

Akira Takashima：“过敏性接触性皮炎”Landes Bioscience（出版中）（2004 年）。

Jean Krutmann, Akimichi Morita: "Phototherapy for Atopic Dermatitis"Marcel Dekker monograph on "Atopic Dermatitis" (edited by Thomas Bieber and Donald Lung). 501-518 (2002)

Jean Krutmann、Akimichi Morita：“特应性皮炎的光疗”Marcel Dekker 关于“特应性皮炎”的专着（由 Thomas Bieber 和 Donald Lung 编辑）。

Yoko Yasuda: "Development of a new protein transduction system by fusing N-terminal peptides of partial Cholera toxin B subunit"Nagoya Medical Journal. 46. 17-26 (2003)

安田洋子：“通过融合部分霍乱毒素 B 亚基的 N 末端肽开发新的蛋白质转导系统”名古屋医学杂志。

Hiroo Sawada: "Altered decorin expression of systemic sclerosis by UVA1 (340400nm) phototherapy : Immunohistochemical analysis of 3 cases"BMC Dermatol. (印刷中).

Hiroo Sawada：“UVA1 (340400nm) 光疗改变系统性硬化症的核心蛋白聚糖表达：3 例免疫组织化学分析”BMC Dermatol（正在出版）。

Li Yin, Akimichi Morita, Takuo Tsuji: "Molecular alterations of tropoelastin and proteoglycan induced by ultraviolet A and tobacco smoke extracts in cultured skin fibroblasts"Nagoya Medical Journal. 45. 63-74 (2002)

Li Yin、Akimichi Morita、Takuo Tsuji：“紫外线 A 和烟草烟雾提取物在培养的皮肤成纤维细胞中诱导原弹性蛋白和蛋白多糖的分子变化”名古屋医学杂志。