HOST RESPONSES TO PHOTODYNAMIC THERAPY

该项目的目标仍然是阐明复杂的机制 构成对光动力疗法（PDT）的组织反应。我们已经做了 PDT 改变 IL-6 和 IL-10 表达的新观察 体内处理组织中的信息和蛋白质；因此我们重点关注这次更新 应用这些影响的机制和后果。的 总体假设是 PDT 通过其氧化应激机制， 在体外影响某些细胞因子的转录调节 在体内，这些效果对于不同的光敏剂是不同的， 取决于细胞内的定位，并且这些变化 细胞因子的表达影响宿主的局部和免疫功能 系统层面。在具体目标 1 中，我们将确定：(a) 是否进行 PDT 细胞因子基因表达的诱导改变取决于光敏剂 类型和本地化。我们期望找到光敏剂（定位）—— 细胞因子反应的依赖性差异与所描述的相似 用于某些早期反应基因的 PDT 反应。 (b)是否PDT 直接影响IL-10基因调控及其分子机制是什么 参与。根据我们体内 IL-10 上调的发现，我们预计 发现 IL-10 基因调控至少在某些方面受到 PDT 的直接影响 提议研究的细胞类型。由于人们对 IL 知之甚少 10个基因调控，本研究将有助于整体了解 IL-10 基因控制以及对其影响的具体了解 的PDT。在特定目标 II 中，我们将确定观察到的变化是否 细胞因子表达影响局部或全身宿主免疫 反应，特别是 PDT 诱导的抗肿瘤反应和 PDT- 抑制接触超敏反应（CHS）。我们将确定 (a) 哪些细胞类型（尤其是肿瘤和皮肤细胞）分泌细胞因子 对体内 PDT 感兴趣； (b) PDT对免疫细胞的影响 组织水平的功能，包括抗原呈递和细胞毒性 和细胞溶解免疫原性； (d)细胞因子是否发生变化 表达，尤其是 IL-6 和 IL-10，参与免疫变化 细胞功能。由于IL-6和IL-10在抗肿瘤和抗肿瘤方面都很重要 CHS 反应，预计 PDT 会引起这些细胞因子的变化 会影响体内的免疫反应。在具体目标 III 中，我们将 确定 PDT 是否引起细胞因子表达的变化以及 临床前观察到的炎症和免疫细胞浸润的变化 也发生在患者身上。这些研究的长期目标是改善 全面了解 PDT 对免疫系统的影响。

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.