Therapeutic immunosuppression,inflammation & skin cancer

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。这包括患有疾病相关免疫抑制的患者，如感染艾滋病毒的患者，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细胞功能减弱，紫外线（UV）诱导的皮肤鳞状细胞癌（SCC）的发展急剧增加。这些患者的鳞状细胞癌发病率不仅高于普通人群，而且每个患者的鳞状细胞癌发病率也有所增加。免疫抑制患者的SCC通常具有很强的侵袭性，死亡率很高。虽然很明显，紫外线照射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细胞反应的减少是如何作为疾病的副产品还是作为治疗的结果，导致SCC的产生。以下具体目标旨在验证以下假设：CD4 t细胞的选择性消耗增加了uvb诱导的皮肤炎症反应，进而导致SCC的早期发病，SCC数量增加，肿瘤的侵袭性增加。这些研究还将检查免疫抑制时间相对于紫外线暴露对SCC发展的重要性。在uvb诱导的SCC发展的SKH-1无毛小鼠模型中，特异性Aim 1研究将通过治疗相关免疫抑制剂环孢素同时暴露于DVB，研究消耗CD4+ t细胞或降低这些细胞功能对uvb诱导的炎症和肿瘤形成的影响。本研究的目的是研究t细胞失调与紫外线暴露同时产生的影响，正如在早期免疫抑制的儿童中所看到的那样，在他们积累大量的UVB暴露之前。特异性Aim 2的研究将检验在UVB暴露10周后开始的CD4* t细胞消耗或环孢素治疗对SKH-1无毛小鼠炎症和肿瘤形成的影响。本研究的目的是研究先前UVB暴露后t细胞失调的影响，正如在免疫抑制之前有明显UVB暴露的成年人中所看到的那样。特异性Aim 3的研究将确定在UVB暴露20周后开始的CD4 t细胞消耗或环孢素治疗对SKH-1无毛小鼠乳头状瘤向SCC进展的影响。本研究旨在探讨t细胞失调对已建立的UVB诱导肿瘤的进展和侵袭性的影响。本研究将有助于阐明CD4* T细胞在UVB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.