Photodynamic Therapy-Induced Immune Modulation: Mechanisms and Influence on Therapeutic Efficacy

从化疗到紫外线等多种环境和医源性促氧化应激源 辐射已被证明在临床前小鼠模型中诱导免疫抑制。这些 应激源也被证明是脂质介体血小板激活因子(PAF)的有效诱导者， 在小鼠模型中发挥免疫抑制作用。我们和其他组织的特点是 PAF依赖的免疫抑制发生的确切途径，并已确定其主要作用 调节性T细胞(Treg)。损伤后释放的PAF作用于肥大细胞的PAF受体，导致 免疫抑制树的形成。这一过程依赖于细胞因子IL-10和 环氧合酶-2(COX-2)产生前列腺素。尽管高水平的PAF已经被证明是 在动物体内对诱发PAF的许多免疫抑制应激源作出反应而产生的 模型，需要研究来确定这种PAFCOX-2Treg途径是否在人类中起作用。此修订版 R21应用程序旨在利用我们小组最近的发现，局部光动力学疗法 (PDT)是一种在小鼠皮肤中非常有效的PAF诱导剂，仅在小鼠体内诱导全身免疫抑制 表达PAF受体。光动力疗法在皮肤科是一种非常常见的程序，已被证明是 对人体的免疫抑制作用。这为测试PAFCOX-2Treg通路提供了理论基础 参与了PDT诱导的效应，并可被COX-2抑制剂药理调节以阻断 免疫抑制和光动力疗法在治疗癌前光化性角化病中的潜在作用 损伤。我们将测试在皮肤科诊所进行的标准光动力疗法是否会产生：1)PAF和相关的氧化 皮肤中的甘油磷胆碱；2)全身异前列腺素对活性氧的反应；以及3) 全身环氧合酶产生的前列腺素。我们还将表征PDT对小鼠的免疫抑制作用。 通过皮肤测试和分析树突状细胞和T细胞对已建立的和新的抗原的反应。 环氧合酶-2抑制剂塞来昔布对光动力疗法后短期光动力疗法的调节作用 免疫抑制和临床有效性也将被定义。因此，这些翻译研究将定义 如果在PDT之后参与了以前未被认识的免疫调节途径，这可以被利用来 提高治疗效果。如果成功，这些研究将改变光动力疗法的护理标准 管理。

Numerous environmental and iatrogenic pro-oxidative stressors ranging from chemotherapy to ultraviolet radiation have been demonstrated to induce immunosuppression in preclinical murine models. These stressors have also been shown to be potent inducers of the lipid mediator platelet-activating factor (PAF), which exerts immunosuppressive effects in murine models. Ours and other groups have characterized the exact pathways by which PAF-dependent immunosuppression occurs and have identified a major role of regulatory T cells (Treg). PAF released from injury acts upon the mast cell PAF receptor resulting in the formation of immunosuppressive Tregs. This process is dependent upon the cytokine IL-10 and cyclooxygenase-2 (COX-2) generated prostaglandins. Though high levels of PAF has been shown to be generated in humans in response to many of the immunosuppressive stressors that induce PAF in animal models, studies are needed to define if this PAFCOX-2Treg pathway is functional in humans. This revised R21 application is designed to take advantage of our group’s recent findings that topical photodynamic therapy (PDT) is a very potent inducer of PAF in murine skin, and induces systemic immunosuppression only in mice expressing PAF receptors. PDT is a very common procedure in dermatology which has been shown to exert immunosuppressive effects in humans. This provides the rationale to test if the PAFCOX-2Treg pathway is involved in PDT-induced effects and could be pharmacologically modulated with COX-2 inhibitors to block the immunosuppression and potentially improve PDT efficacy in treating precancerous actinic keratoses lesions. We will test if standard PDT performed in dermatology clinics generates: 1) PAF and related oxidized glycerophosphocholines in skin; 2) systemic isoprostanes in response to reactive oxygen species; and 3) systemic COX-produced prostaglandins. We will also characterize the immunosuppressive effects of PDT in humans by both skin testing, and assaying Tregs and T cell responses against established and neo-antigens. The ability of short-term post-PDT treatment with the COX-2 inhibitor celecoxib to modulate PDT-mediated immunosuppression and clinical effectiveness will also be defined. These translational studies will thus define if a previously unappreciated immunomodulatory pathway is engaged following PDT which can be exploited to enhance treatment outcomes. If successful, these studies will change the standard of care for how PDT is administered.