权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

UROCANIC ACID, SUNLIGHT & IMMUNITY--A NOVEL INTERACTION

尿刊酸、阳光

基本信息

批准号：
2414215
负责人：
EDWARD C DEFABO
金额：
$ 27.85万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-12-04 至 1999-04-30
项目状态：
已结题

项目摘要

Ultraviolet B radiation (UVB) contains the shortest wavelengths of sunlight penetrating to the Earth's surface (290-320nm). These wavelengths are directly linked to skin cancer formation and immunological alterations leading to systemic immunosuppression in mammals. Experimental studies strongly link this suppression to skin cancer. Irradiation of the skin with UVB is systemically suppressive of contact hypersensitivity reactions (CHS) to chemicals, delayed type hypersensitivity responses (DTH) to hapten-conjugated cells, to viruses, and to parasites. UV irradiation also suppresses the DTH response to alloantigens, and has been shown to prolong experimental allograft acceptance. UV suppression prevents the immunologic rejection of highly antigenic UV tumors. We proposed that immune suppression of T-cell immunity is protective and evolved to prevent autoimmune attack against skin cells containing sunlight-induced "photoantigens". UV suppression provides time to synthesize new skin without the "photoantigens". This hypothesis predicts that too much sun exposure could lead to inadvertent protection of any pre-existing skin tumor cells as well. Our research has been aimed at understanding the mechanism by which UV radiation induces immunosuppression. Our most critical finding was that suppression of CHS was mediated by the presence, on the outermost layer of skin, of an unusual photoreceptor capable of initiating immune suppression. We identified this photoreceptor as urocanic acid (UCA), de-aminated histidine. In this proposal we expand our studies to include (i) the effects of UV radiation on cytokine induction and localization; cytokines are important immunoregulatory signals recently shown to be activated by UVB irradiation of skin; (2) studies to isolate and identify the cell receptor for cis UCA binding; experimental evidence indicates this to be the moiety which initiates immune suppression and to study the mechanism of antigen-presenting cell alteration by UV and cis UCA; (3) the effects of UVA radiation on UVB- induced immune suppression since UVA may modulate the expression of UVB- induced suppressor signals through the UVA-UVB ratio which changes throughout sunlight exposure; and (4) the effects of the amino acid L- histidine on skin cancer because of its ability to enhance immune suppression through cis UCA formation. Significance:UV-induced immune suppression has now been confirmed in humans and appears to be independent of pigmentation. In addition to skin cancer growth, the development of certain types of cell-mediated infectious diseases appear to be influenced by UV suppression. Recently published laboratory experiments indicate a potential role for UV-B,cis UCA in delaying the rejection of transplanted tissue. This opens up the possibility of using UCA as a therapeutic agent in delaying the rejection of transplanted organs and tissues. Finally, significant stratospheric ozone reduction has become a reality over populated areas of the Northern Hemisphere. We recently showed that the doses of UVB used experimentally to induce suppression can be achieved by natural sunlight exposure over most populated countries between 40 N and 40 S in summertime. Immune suppressing solar UVB irradiances may, therefore, be expected to increase by stratospheric ozone depletion over large populated areas of the world. Given the significant losses of ozone over the U.S. during summer 1993 (10-20%) this may have already occurred.

紫外线B辐射（UVB）包含最短波长的阳光穿透地球表面（290- 320 nm）。这些波长与皮肤癌的形成和免疫学改变直接相关导致哺乳动物的全身性免疫抑制。实验研究将这种抑制与皮肤癌联系起来。皮肤辐射 UVB对接触性超敏反应具有全身抑制作用 (CHS)迟发型超敏反应（DTH）半抗原结合的细胞、病毒和寄生虫。UV照射还抑制对同种异体抗原的DTH反应，实验性同种异体移植物接受紫外线抑制可以阻止免疫系统排斥高抗原性UV肿瘤。我们提出免疫抑制T细胞免疫是保护性的，并进化为防止自身免疫攻击皮肤细胞含有阳光诱导 “光抗原”。紫外线抑制提供时间来合成新的皮肤没有“光抗原”。这一假说预测，暴露可能导致对任何预先存在的皮肤的无意保护肿瘤细胞也是。我们的研究旨在了解紫外线辐射诱导免疫抑制的机制。我们最关键的发现是CHS的抑制是通过存在，在皮肤的最外层，有一种不寻常的感光器，启动免疫抑制我们鉴定出这种感光细胞尿刊酸（UCA）、脱氨基组氨酸。在本建议中，我们扩大了我们的研究包括（i）紫外线辐射对细胞因子诱导的影响细胞因子是重要的免疫调节信号最近被证明是由UVB照射皮肤激活;（2）研究，分离并鉴定用于顺式UCA结合的细胞受体;实验有证据表明，这是启动免疫的部分，研究抗原提呈细胞的作用机制紫外线和顺式UCA的改变;（3）UVA辐射对UVB- 由于UVA可以调节UVB的表达，通过UVA-UVB比率的变化诱导抑制信号整个阳光照射;和（4）氨基酸L- 组氨酸对皮肤癌的作用，因为它能够增强免疫通过顺式UCA形成抑制。意义：紫外线诱导免疫抑制现在已被证实在人类，似乎是独立的色素沉着。除了皮肤癌的生长外，某些类型的细胞介导的感染性疾病似乎受到紫外线抑制。最近发表的实验室实验表明， UV-B，cis UCA在延缓移植排斥反应中的潜在作用组织.这开辟了使用UCA作为治疗剂的可能性延缓移植器官和组织的排斥反应。最后，平流层臭氧大幅度减少已成为现实，北方半球人口稠密的地区。我们最近发现，实验上用于诱导抑制的UVB剂量可以通过以下方式实现：在大多数人口稠密的国家，自然阳光照射在40 N和 40岁的夏天免疫抑制太阳UVB辐射可以，因此，预计随着平流层臭氧消耗的增加，世界上人口众多的地区。考虑到臭氧的大量流失在1993年夏天，美国上空的这种情况（10-20%）可能已经发生了。