Therapeutic immunosuppression,inflammation & skin cancer

描述(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。这些患者包括与疾病相关的免疫抑制患者，如艾滋病毒感染者，以及那些接受长期治疗性免疫抑制的患者，包括移植患者和炎症性和自身免疫性疾病患者。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细胞功能受抑，紫外线(UV)诱导的皮肤鳞状细胞癌(SCC)的发展急剧增加。不仅这些患者的鳞癌发病率高于普通人群，而且每个患者发生的鳞癌的数量也在增加。在免疫抑制的90名患者中出现的鳞状细胞癌通常非常具有侵袭性，并与相当大的死亡率相关。虽然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细胞反应减弱，无论是疾病的副产品还是治疗的结果，如何促成鳞状细胞癌的产生。以下特定目的旨在验证选择性耗尽CD4T细胞增加UVB诱导的皮肤炎症反应，进而导致SCC发病更早、SCC数量增加和肿瘤侵袭性增加的假设。这些研究还将检验相对于紫外线暴露的免疫抑制时机对鳞状细胞癌发生的重要性。特定目标1的研究将在紫外线诱导的无毛小鼠鳞状细胞癌发展的SKH-1模型中，通过在DVB暴露的同时使用治疗相关的免疫抑制剂环孢菌素来检测耗尽CD4T细胞或降低这些细胞的功能对UVB诱导的炎症和肿瘤形成的影响。这一目的是研究在紫外线暴露的同时T细胞调节失调的影响，就像在早期免疫抑制的儿童中看到的那样，他们还没有积累大量的紫外线暴露。在特定目标2中的研究将检验在UVB暴露10周后开始的CD4*T细胞耗尽或环孢素治疗对SKH-1无毛小鼠炎症和肿瘤形成的影响。这项研究的目的是研究先前UVB暴露后T细胞调节失调的影响，就像在免疫抑制之前有大量UVB暴露的成年人所看到的那样。具体目标3的研究将确定在紫外线照射20周后开始的CD4T细胞耗尽或环孢素A治疗对SKH-1无毛小鼠乳头状瘤向鳞状细胞癌发展的影响。本研究的目的是研究T细胞失调对已建立的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细胞在中波紫外线诱导的炎症和皮肤癌变过程中的作用。

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.