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）：在过去的30年里，免疫抑制患者的数量出现了前所未有的增长。这些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，包括移植患者和患有炎症和自身免疫性疾病的患者。虽然这些患者的免疫抑制程度差异很大，但共同的发现是T细胞功能的抑制和紫外线（UV）诱导的皮肤鳞状细胞癌（SCC）的发展急剧增加。这些患者不仅SCC的发病率高于一般人群，而且每个患者发生SCC的数量也增加。在免疫抑制的90例患者中出现的SCC通常非常具有侵袭性，并与大量死亡率相关。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作为治疗的结果，都有助于SCC的产生。以下具体目的旨在检验以下假设：选择性消耗CD 4 T细胞会增加皮肤中UVB诱导的炎症反应，进而导致SCC的早期发作、SCC数量增加和肿瘤侵袭性增加。这些研究还将检查免疫抑制的时间相对于紫外线暴露对SCC发展的重要性。具体目标1的研究将在UVB诱导SCC发展的SKH-1无毛小鼠模型中，通过用治疗相关的免疫抑制剂环孢菌素治疗同时DVB暴露，检查CD 4 + T细胞耗竭或这些细胞功能降低对UVB诱导的炎症和肿瘤形成的影响。这一目的是检查T细胞失调的影响，同时与紫外线照射，将看到在儿童谁是免疫抑制的早期生活，之前他们已经积累了大量的UVB照射。特定目标2的研究将检查UVB暴露10周后开始的CD 4 * T细胞消耗或环孢菌素治疗对SKH-1无毛小鼠炎症和肿瘤形成的影响。这个目的是检查先前UVB暴露后T细胞失调的影响，正如在免疫抑制之前有显著UVB暴露的成年人中所看到的那样。特定目标3的研究将确定在SKH-1无毛小鼠中，UVB暴露20周后开始的CD 4 T细胞耗竭或环孢霉素治疗对乳头状瘤向SCC进展的影响。 本研究旨在检测T细胞失调对UVB诱导肿瘤进展和侵袭性的影响。本研究将有助于阐明CD 4 * T细胞在UVB诱导的炎症反应以及皮肤癌变过程中的作用。