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）的组织响应。我们取得了 PDT改变IL-6和IL-10表达新观察 信息和蛋白质在体内治疗的组织;因此，我们专注于这种更新 这些影响的机制和后果的应用。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，这些效应对于不同的光敏剂是不同的， 取决于细胞内的定位，这些变化， 细胞因子的表达影响宿主的免疫功能， 系统层面。在具体目标1中，我们将确定：（a）PDT是否 光敏剂诱导细胞因子基因表达的改变 类型和定位。我们希望找到光敏剂（定位）- 细胞因子反应的依赖性差异类似于 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， 涉案基于我们体内IL-10上调的发现，我们预期 发现IL-10基因调控在至少一些细胞中直接受到PDT的影响， 研究的细胞类型。由于我们对它知之甚少， 10基因调控，这项研究将有助于全面了解 IL-10基因控制以及对IL-10基因的影响的具体理解 的PDT。在具体目标II中，我们将确定观察到的变化是否 在细胞因子表达影响局部或全身宿主免疫 在一些实施方案中，所述方法包括： 抑制接触性超敏反应（CHS）。我们将确定（a） 哪些细胞类型（特别是在肿瘤和皮肤中）分泌 （B）PDT对免疫细胞的影响 在组织水平上的功能，包括抗原呈递和细胞毒性 和细胞溶解免疫原性;（d）以及细胞因子 表达，特别是IL-6和IL-10，参与免疫系统的变化， 细胞功能由于IL-6和IL-10在抗肿瘤和抗肿瘤治疗中都是重要的， CHS反应，预期PDT诱导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是否诱导细胞因子表达的变化， 临床前观察到的炎症和免疫细胞浸润的变化 也发生在病人身上。这些研究的长期目标是改善 对PDT对免疫系统影响的全面了解。

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.