Do NKT cells mediate UV induced Immune Suppression?

NKT 细胞介导紫外线诱导的免疫抑制吗？

• 批准号: 6759349
• 负责人: Stephen E ULLRICH
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6759349
• 关键词: CD1 molecule; interleukin 10; interleukin 12; interleukin 2; interleukin 4; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; passive immunization; prostaglandin E; radiation carcinogenesis; radiation immunosuppression; skin neoplasms; suppressor T lymphocyte; ultraviolet radiation; urocanate

DESCRIPTION: (provided by applicant): - In addition to being a complete carcinogen, exposure to ultraviolet (UV) radiation is immunosuppressive. Studies with both experimental animals and biopsy proven skin cancer patients have indicated that the immune suppression induced by UV radiation is a major risk factor for skin cancer development. Exposing mice to subcarcinogenic doses of UV suppresses their immune response and allows for the outgrowth of UV-induced skin cancers. This immune suppression can be transferred to normal recipients by adoptive transfer of splenic CD3+, CD4+, CD8- suppressor T cells (UV-Ts), cells that are also responsible for controlling the induction of the primary tumor in the UV-irradiated host. One glaring gap in our knowledge of the mechanism(s) by which UV exposure suppresses tumor immunity is the incomplete understanding of the exact identity and function of UV-Ts. Previous studies from this laboratory indicate that one mechanism by which UV-Ts down-regulate immunity is by interleukin (IL)-2 secretion. According to current immunological literature, only two T cell subsets readily secrete IL-4, T heIper-2 cells, and natural killer T (NKT) cells. Because of unique surface markers on NKT cells, it is possible to separate T helper-2 cells from NKT cells. Our preliminary findings indicate that a highly purified population of NK1 cells can transfer suppression of tumor immunity from UV-irradiated mice to normal recipients. The focus of this grant proposal is to test the hypothesis that UV-Ts are NKT cells. The specific alms of this grant are designed to answer the following questions: 1) Are UV-Ts NKT cells? 2) How do NKT cells suppress tumor rejection? 3) Is the activation of UV-induced NKT cells CD1 restricted? 4) How does the altered cytokine environment found in UV-irradiated mice affect the induction/activation of NKT cells? 5) Is it possible to clone NKT cells with suppressive activity from the lymphoid organs of UV-irradiated mice? The long-term goal of this research is to determine how UV exposure induces systemic immune suppression and permits the outgrowth of skin cancer. Because there is a link between the ability of UV exposure to suppress immunity and induce skin cancer, it is critically important to understand how these immune regulatory cells function to suppress immunity and promote cancer development. A better understanding of the mechanisms involved in UV-induced immune suppression may help with the design of rational approaches to block immune suppression, thereby reducing one of the major risk factors for skin cancer induction.

描述：（由申请人提供）： - 除了完整 致癌，暴露于紫外线（UV）辐射是免疫抑制的。 实验动物和活检证明的皮肤癌患者的研究 已经表明，紫外线辐射引起的免疫抑制是主要的 皮肤癌发展的危险因素。将小鼠暴露于亚癌症剂量 紫外线抑制其免疫反应，并允许生长 紫外线引起的皮肤癌。这种免疫抑制可以转移到正常 接收者通过脾脏CD3+，CD4+，CD8-抑制T细胞转移 （UV-TS），也负责控制诱导的细胞 紫外线辐射宿主中的原发性肿瘤。 我们对紫外线暴露的机制的了解的一个明显的差距 抑制肿瘤免疫是对确切身份的不完全理解 和UV-TS的功能。该实验室的先前研究表明 UV-TS下调免疫力的机制是白介素（IL）-2 分泌。根据当前的免疫学文献，只有两个T细胞 子集很容易分泌IL-4，t Heiper-2细胞和自然杀手t（NKT） 细胞。由于NKT单元格上独特的表面标记，因此可以 将T辅助2细胞与NKT细胞分开。我们的初步发现表明 高度纯化的NK1细胞群可以转移 从紫外线辐射小鼠到正常受体的肿瘤免疫。重点 授予建议是检验UV-TS是NKT细胞的假设。具体 赠款的施舍旨在回答以下问题：1）是UV-TS NKT细胞？ 2）NKT细胞如何抑制肿瘤排斥？ 3）激活是 紫外线诱导的NKT细胞CD1受到限制？ 4）如何改变细胞因子 在紫外线辐射小鼠中发现的环境会影响NKT的诱导/激活 细胞？ 5）是否有可能从抑制活性的NKT细胞中 紫外线的小鼠的淋巴器官？ 这项研究的长期目标是确定紫外线暴露如何引起 全身性免疫抑制并允许皮肤癌的生长。因为 紫外线暴露于抑制免疫力的能力与 诱发皮肤癌，了解这些免疫是至关重要的 调节细胞的功能可抑制免疫力并促进癌症发展。 更好地理解紫外线诱导的免疫的机制 抑制可能有助于设计理性方法以阻止免疫力 抑制作用，从而减少了皮肤癌的主要危险因素之一 就职。