HOST RESPONSES TO PHOTODYNAMIC THERAPY

宿主对光动力疗法的反应

• 批准号: 6269519
• 负责人: BARBARA W. HENDERSON
• 金额: $ 21.42万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269519
• 关键词: cytotoxicity; drug screening /evaluation; human tissue; interleukin 10; interleukin 6; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; nonvisual photosensitivity; oxidative stress; photosensitizing agents; radiotracer; tumor antigens

The goal of this project remains to elucidate the complex mechanisms which constitute the tissue response to photodynamic therapy (PDT). We have made the novel observation that PDT alters the expression of IL-6 and IL-10 message and protein in treated tissues in vivo; thus we focus this renewal application on the mechanisms and consequences of these effects. The overall hypothesis are that PDT, via its oxidative stress mechanisms, affects the transcriptional regulation of certain cytokines in vitro and in vivo, that these effects differ for different photosensitizers, depending on intracellular localizations, and that these changes in cytokine expression affect host immune function at both the local and systemic level. In Specific Aim 1 we will determine:(a) Whether PDT induced alterations in cytokine gene expression depend on photosensitizer type and localization. We expect to find photosensitizer (localization)- dependent differences in the cytokine response similar to those described for the PDT response of certain early response genes. (b) Whether PDT affects IL-10 gene regulation directly and what molecular mechanisms are involved. Based on our in vivo findings of IL-10 upregulation we expect to find IL-10 gene regulation to be directly affected by PDT in at least some of the cell types proposed for study. Since very little is known about IL- 10 gene regulation, this study will contribute to an overall understanding of IL-10 gene control as well as to specific understanding of the effects of PDT. In Specific Aim II we will determine whether the observed changes in cytokine expression influence the local or systemic host immune response, in particular the PDT-induced anti-tumor response and the PDT- suppressed contact hypersensitivity (CHS) response. We will determine (a) which cell types (especially in tumor and skin) secrete the cytokines of interest following PDT in vivo; (b) the effect of PDT on immune cell function at the tissue level, including antigen presentation and cytotoxic and cytolytic immunogenicity; (d) and whether changes in cytokine expression, especially IL-6 and IL-10, are involved in changes in immune cell function. Since both IL-6 and IL-10 are important in anti-tumor and CHS responses, it is expected that PDT induced changes in these cytokines will affect the immune response in vivo. In Specific Aim III we will determine whether the PDT induced changes in cytokine expression and changes in inflammatory and immune cell infiltrates observed preclinically also occur in patients. These studies have the long term goal of improving the overall understanding of the effect of PDT on the immune system.

该项目的目标仍然是阐明复杂机制 构成对光动力疗法（PDT）的组织反应。我们做了 PDT改变了IL-6和IL-10的表达的新颖观察结果 在体内处理的组织中的消息和蛋白质；因此，我们集中于这个更新 应用这些影响的机制和后果。这 总体假设是PDT通过其氧化应激机制， 影响某些细胞因子在体外的转录调节，并且 在体内，这些效果在不同的光敏剂中有所不同， 取决于细胞内定位，并且这些变化 细胞因子表达会影响局部和 系统水平。在特定目标1中，我们将确定：（a）PDT是否 诱导的细胞因子基因表达的改变取决于光敏剂 类型和本地化。我们希望找到光敏剂（本地化） - 类似于描述的细胞因子反应的依赖性差异 对于某些早期反应基因的PDT响应。 （b）是否PDT 直接影响IL-10基因调节，哪些分子机制是 涉及。基于我们的体内IL-10上调的发现，我们期望 查找至少在某些中直接影响PDT的IL-10基因调节 提议研究的细胞类型。因为关于IL的知之甚少 10基因调节，这项研究将有助于整体理解 IL-10基因控制以及对影响的特定理解 PDT。在特定的目标II中，我们将确定观察到的变化是否变化 在细胞因子表达中影响局部或全身宿主免疫 响应，特别是PDT诱导的抗肿瘤反应和PDT- 抑制接触超敏反应（CHS）反应。我们将确定（a） 哪种细胞类型（尤其是在肿瘤和皮肤中）分泌的细胞因子 PDT在体内的兴趣； （b）PDT对免疫细胞的影响 组织水平的功能，包括抗原表现和细胞毒性 和细胞溶解免疫原性； （d）以及细胞因子的变化是否变化 表达，特别是IL-6和IL-10，与免疫变化有关 细胞功能。由于IL-6和IL-10都在抗肿瘤中很重要，并且 CHS响应，预计PDT会诱导这些细胞因子的变化 将影响体内免疫反应。在特定的目标III中，我们将 确定PDT是否诱导细胞因子表达和 观察到的炎症和免疫细胞浸润的变化 也发生在患者中。这些研究的长期目标是改善 PDT对免疫系统的影响的总体理解。