HOST RESPONSES TO PHOTODYNAMIC THERAPY

这个项目的目标仍然是阐明 构成对光动力疗法(PDT)的组织反应。我们已经做出了 光动力疗法改变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；因此我们关注这一更新 关于这些影响的机制和后果的应用。这个 总体假设是，光动力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，这些效应对于不同的光敏剂是不同的， 取决于细胞内的定位，以及这些变化在 细胞因子的表达在局部和局部影响宿主免疫功能 系统层面。在具体目标1中，我们将确定：(A)光动力疗法 光敏剂对细胞因子基因表达的诱导作用 类型和本地化。我们希望找到光敏剂(本地化)- 细胞因子反应的依赖差异类似于所描述的 某些早期反应基因的光动力反应。(B)PDT是否 直接影响IL-10基因调控及其分子机制 牵涉其中。根据我们在体内发现的IL-10上调，我们预计 发现IL-10基因调控至少在某些情况下直接受PDT的影响 建议研究的细胞类型。由于人们对IL知之甚少， 10基因调控，这项研究将有助于全面了解 IL-10基因调控以及对其影响的具体理解 光动力疗法。在特定目标二中，我们将确定观察到的变化 细胞因子的表达影响局部或系统的宿主免疫 反应，特别是PDT诱导的抗肿瘤反应和PDT- 抑制接触性超敏反应。我们将决定(A) 哪些细胞类型(特别是在肿瘤和皮肤中)分泌的细胞因子 体内对光动力疗法的兴趣；(B)光动力疗法对免疫细胞的影响 在组织水平上的功能，包括抗原提呈和细胞毒性 和细胞免疫原性；(D)以及细胞因子是否发生变化 表达，尤其是IL-6和IL-10参与了免疫功能的变化 细胞功能。由于IL-6和IL-10在抗肿瘤和 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。在第三个具体目标中，我们将 确定PDT是否诱导了细胞因子表达的变化和 临床前观察到的炎性细胞和免疫细胞浸润的变化 也会发生在病人身上。这些研究都有改进的长期目标 全面了解光动力疗法对免疫系统的影响。

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.