Therapeutic immunosuppression,inflammation & skin cancer

治疗性免疫抑制、炎症

• 批准号: 7048461
• 负责人: TATIANA M OBERYSZYN
• 金额: $ 25.95万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048461
• 关键词: adult human (21+); artificial immunosuppression; children; cutaneous papilloma; cyclosporines; disease /disorder model; environmental exposure; helper T lymphocyte; immunosuppressive; inflammation; laboratory mouse; mixed lymphocyte reaction test; neoplasm /cancer immunology; neoplastic process; radiation related neoplasm /cancer; skin neoplasms; squamous cell carcinoma; ultraviolet radiation

DESCRIPTION (provided by applicant): The past 30 years have seen unprecedented growth in the numbers of immunosuppressed patients. These include patients with disease-related immunosuppression, such as those infected with HIV, as well as those receiving long-term therapeutic immunosuppression including transplant patients and patients with inflammatory and autoimmune disorders. While the degree of immunosuppression varies considerably among these patients, common findings are a dampening of T-cell function and a dramatic increase in the development of ultraviolet light (UV)-induced cutaneous squamous cell carcinoma (SCC). Not only is the incidence of SCC higher in these patients than in the general population but the number of SCC that develop in each patient is increased. The SCC arising in immunosuppressed 90 patients are often very aggressive and are associated with substantial mortality. While it is clear that UV exposure and immunosuppression are major factors in the development of cutaneous malignancies, it is not clear how diminished T cell responses, either as a byproduct of disease or as a result of therapy, contributes to the generation of SCC. The following specific aims are designed to test the hypothesis that selective depletion of CD4 T-cells increases the UVB-induced inflammatory response in the skin and that this, in turn, results in an earlier onset of SCC, increased numbers of SCC, and increased aggressiveness of the tumors. These studies will also examine the importance of timing of immunosuppression relative to UV exposure on SCC development. Studies in specific Aim 1 will examine the effects of depleting CD4+ T-cells or decreasing function of these cells by treating with the therapeutically relevant immunosuppressive agent cyclosporine concurrently with DVB exposure on UVB-induced inflammation and tumor formation, in an SKH-1 hairless mouse model of UVB-induced SCC development. This aim examines the effects of T-cell dysregulation concurrently with UV exposure, as would be seen in children who are immunosuppressed early life, before they have accumulated substantial UVB exposure. Studies in specific Aim 2 will examine the effects of CD4* T-cell depletion or cyclosporine treatment begun after 10 weeks of UVB exposure on inflammation and tumor formation in SKH-1 hairless mice. This aim examines the effects of T-cell dysregulation following prior UVB exposure, as would be seen in adults who have had significant UVB exposure prior to immunosuppression. Studies in specific Aim 3 will determine the effects of CD4 T-cell depletion or cyclosporine treatment begun after 20 weeks of UVB exposure on the progression of papillomas to SCC in SKH-1 hairless mice. This aim examines the effects of T-cell dysregulation on the progression and aggressiveness of established UVB induced tumors. The studies in the present proposal will help to clarify the role of CD4* T cells in UVB induced inflammation as well as in the cutaneous carcinogenesis process.

描述（由申请人提供）：过去30年来，免疫抑制患者的数量空前增长。其中包括患有疾病相关免疫抑制的患者，例如感染HIV的患者，以及接受长期治疗性免疫抑制的患者，包括移植患者和炎症和自身免疫性疾病的患者。尽管这些患者的免疫抑制程度差异很大，但常见发现是T细胞功能的衰减以及紫外光光（UV）诱导的皮肤皮肤鳞状细胞癌（SCC）的急剧增加。这些患者中SCC的发病率不仅比普通人群高，而且每个患者中出现的SCC数量增加。在免疫抑制的90例患者中产生的SCC通常非常侵略性，并且与大量死亡有关。虽然很明显，紫外线暴露和免疫抑制是皮肤恶性肿瘤发展的主要因素，但尚不清楚T细胞反应的减少，无论是作为疾病的副产品还是治疗导致的，都会导致SCC产生。以下特定目的旨在检验以下假设：CD4 T细胞的选择性耗竭会增加皮肤中UVB诱导的炎症反应，而这又导致SCC的早期发作，SCC的数量增加，肿瘤的侵略性增加。这些研究还将研究免疫抑制时间与紫外线暴露对SCC发育的重要性。在特定目标1中的研究将检查通过使用治疗相关的免疫抑制剂环孢素与DVB暴露对UVB诱导的炎症和肿瘤形成，在SKH-1无毛小鼠诱导的SCC诱导的SCC诱导的SCC诱导的SCCH-1无毛的模型中，通过与DVB暴露的治疗相关的免疫抑制剂环孢菌素同时处理耗尽的CD4+ T细胞或降低这些细胞的功能的影响。这个目的研究了T细胞失调与紫外线暴露的作用，在被免疫抑制的早期生活的儿童积累大量UVB暴露之前所见。特定目标2中的研究将检查CD4* T细胞耗竭或环孢菌素治疗在UVB暴露10周后开始对SKH-1无毛小鼠炎症和肿瘤形成的影响。这个目的检查了先前UVB暴露后T细胞失调的影响，如在免疫抑制之前发生UVB明显暴露的成年人所见。在特定目标3中的研究将确定CD4 T细胞耗竭或环孢素治疗在UVB暴露20周后开始对SKH-1无毛小鼠乳头状瘤向SCC进展的影响。 这个目的研究了T细胞失调对已建立UVB诱导肿瘤的进展和攻击性的影响。本提案中的研究将有助于阐明CD4* T细胞在UVB诱导的炎症以及皮肤致癌过程中的作用。