UROCANIC ACID, SUNLIGHT & IMMUNITY: A NOVEL INTERACTION

紫外线辐射（UV）在体内引起选择性全身免疫 镇压 我们建议研究这一机制， 抑制被激活。 我们将检验紫外线诱导的 抑制是由一种不寻常的调节机制启动的， 尿刊酸（UCA）在皮肤中的光异构化如下：（I）. 我们 表明免疫抑制是由异构化（反式）开始的， 顺式）的UCA，随后UVB吸收（290- 320 nm）。 一种独特的老鼠 UCA基因缺陷将与 相应的正常小鼠和接触性超敏反应（CHS） 测定 一种新的窄带紫外光源将用于照射。 我们以前已经表明，在紫外线照射的正常小鼠接触， 在未照射部位敏化，CHS反应在 剂量依赖性方式，波长依赖性对应于 UCA的吸收光谱。 因此，缺乏UCA的小鼠应该表现出 CHS的UV抑制很少或没有。 （二）. Cis UCA，假设 将免疫反应性光产物给予正常人和UCA 缺陷型小鼠通过经皮和皮下给药系统。 顺式UCA 预测在正常和UCA缺陷动物中抑制CHS。 （三）。 使用HPLC，UV后皮肤中的顺式UCA的形成将被检测到。 确定其是否具有剂量和波长依赖性 这与UV诱导的免疫抑制相当。 稳态 将测定UV后UCA的两种异构体在体内的形成。 （四）。 我们将调查内部是否存在反式或顺式UCA 器官和组织，如果顺式UCA从皮肤定位到淋巴 机关 新的初步数据大大增加了修订后的提案 加强了反式UCA对UVB吸收的假设， 免疫抑制 皮肤UCA缺陷的小鼠用 宽波段UVB的抑制作用明显低于同类野生型， 类型. 相反，通过组氨酸负载增加皮肤UCA水平 对于给定量的UVB，免疫抑制显著增加。 进一步证实我们的假设将证实 哺乳动物皮肤中的免疫调节光感受器，其能够启动 抗原特异性抑制性T细胞形成。 此种机制 以前未知，可能对皮肤病等疾病有影响， 癌症、自身免疫紊乱和与紫外线辐射有关的疾病。

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.