UROCANIC ACID, SUNLIGHT & IMMUNITY: A NOVEL INTERACTION

尿刊酸、阳光

• 批准号: 3198427
• 负责人: EDWARD C DEFABO
• 金额: $ 20.8万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-12-04 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3198427
• 关键词: cis trans isomerization; genetic strain; high performance liquid chromatography; hypersensitivity; immunoregulation; nonvisual photoreceptor; physical chemical interaction; radiation carcinogenesis; radiation dosage; radiation immunosuppression; radiation sensitivity; skin neoplasms; suppressor T lymphocyte; ultraviolet radiation; urocanate

Ultraviolet radiation (UV) in vivo causes a selective systemic immune suppression. We propose to investigate the mechanism by which this suppression is activated. We will test the hypothesis that UV-induced suppression is initiated by an unusual regulatory mechanism involving the photoisomerization of urocanic acid (UCA) in the skin as follows: (I). We suggest that immunosuppression is started by the isomerization (trans to cis) of UCA following UVB absorption (290-320nm). A unique strain of mouse genetically deficient in UCA will be irradiated in parallel with corresponding normal mice and the contact hypersensitivity (CHS) response determined. A novel source of narrow band UV will be used for irradiation. We have previously shown that in UV irradiated normal mice contact sensitized on an unirradiated site, the CHS response is suppressed in a dose-dependent manner with a wavelength dependence corresponding to the absorption spectrum of UCA. Mice deficient in UCA should therefore show little or no UV suppression of CHS. (II). Cis UCA, the postulated immunoreactive photoproduct will be administered to normal and to UCA deficient mice by transdermal and subcutaneous delivery systems. Cis UCA is predicted to suppress CHS in both normal and UCA deficient animals. (III). Using HPLC, the formation of cis UCA in the skin after UV will be determined to establish if it has a dose and wavelength dependence comparable to that derived for UV-induced immune suppression. Steady state formation of both isomers of UCA in vivo after UV will be determined. (IV). We will investigate if trans or cis UCA can be found in internal organs and tissue and if cis UCA localizes from the skin to the lymphoid organs. New preliminary data added to the revised proposal greatly strengthens the hypothesis that UVB absorption by trans-UCA initiates immune suppression. The mice deficient in skin UCA irradiated with broadband UVB showed significantly less suppression than congenic wild- type. Conversely, increasing skin UCA levels by histidine loading significantly increased immune suppression for a given amount of UVB. Further verification of our hypothesis will substantiate the existence of an immunoregulatory photoreceptor in mammalian skin capable of initiating antigen-specific suppressor T cell formation. Such a mechanism was previously unknown and may have implications for diseases such as skin cancer, auto-immune disorders and diseases related to UV radiation.

紫外线辐射（UV）在体内引起选择性全身免疫