UROCANIC ACID, SUNLIGHT & IMMUNITY: A NOVEL INTERACTION

尿刊酸、阳光

• 批准号: 3198431
• 负责人: EDWARD C DEFABO
• 金额: $ 17.22万
• 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 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3198431
• 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; transdermal drug delivery; 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.

体内的紫外线辐射(UV)会引起选择性的系统免疫 压制。我们建议调查这一现象的机制 抑制被激活。我们将检验紫外线诱导的假说 压制是由一种不寻常的监管机制启动的，涉及 尿毒酸(UCA)在皮肤中的光异构化反应如下：(I)我们 提示免疫抑制是由异构化开始的(反式到 UVB吸收(290-320 nm)后的顺式)。一种独特的老鼠品系 遗传缺陷的UCA将与辐射同时进行 相应的正常小鼠和接触性超敏反应(CHS) 下定决心。一种新型的窄带紫外光光源将用于辐射。 我们之前已经证明，在紫外线照射的正常小鼠中， 在未受辐射的部位敏化，CHS反应在 剂量依赖的方式，波长依赖关系对应于 UCA的吸收光谱。因此，缺乏UCA的小鼠应该表现出 CHS的紫外线抑制很少或没有。(Ii)。独联体UCA，假设 免疫活性光产物将用于正常和UCA。 通过经皮和皮下给药系统给药的缺陷小鼠。独联体UCA 预计可抑制正常动物和UCA缺陷动物的CHS。 (三)。使用高效液相色谱法，紫外线照射后皮肤中顺式UCA的形成将是 决心确定它是否与剂量和波长有关 与紫外线诱导的免疫抑制作用相当。稳态 紫外线照射后，UCA的两种异构体在体内的形成将被确定。 (四)。我们将调查在内部是否可以找到反式或顺式UCA 器官和组织，如果顺式UCA定位于从皮肤到淋巴组织 器官。新的初步数据大大增加了修订后的提案 强化了UVB被反式UCA吸收的假设 免疫抑制。UCA照射皮肤缺陷小鼠的实验研究 宽带UVB的抑制率明显低于同源野生型UVB 打字。相反，通过组氨酸负荷增加皮肤UCA水平 显著增强了特定剂量的UVB的免疫抑制作用。 进一步验证我们的假设将证实 哺乳动物皮肤中一种能够启动免疫调节的光感受器 抗原特异性抑制T细胞的形成。这样一种机制就是 以前不为人知，可能对皮肤等疾病有影响 癌症、自身免疫紊乱和与紫外线辐射有关的疾病。