权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

光动力疗法诱导的免疫调节：机制及其对疗效的影响

基本信息

批准号：
9300833
负责人：
COURTNEY Elizabeth Williams SULENTIC
金额：
$ 16.28万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9300833
关键词：
Acids Actinic keratosis Agonist Animal Model Antigens Area Attenuated Basal cell carcinoma Biological Assay Candida Clinic Clinical Clinical effectiveness Cyclooxygenase Inhibitors Dermatologic Dermatology Dinitrochlorobenzene Dose Effectiveness Erinaceidae Future Herpes Simplex Infections Human Hypersensitivity skin testing Iatrogenesis Immune Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents Inflammatory Injury Interferon Type II Interleukin-10 Intervention Investigation Ionizing radiation Isoprostanes Lesion Light Mediating Modality Modeling Mus Oxides PTGS2 gene PUVA Photochemotherapy Pathway interactions Patients Pharmacology Photosensitivity Pilot Projects Platelet Activating Factor Play Premalignant Procedures Process Production Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins R-factor Radiation therapy Reactive Oxygen Species Recurrence Regulatory T-Lymphocyte Reporting Role Skin Skin Cancer Source T cell response Testing Therapeutic Therapeutic Effect Time Treatment Efficacy Treatment outcome Trichophyton Ultraviolet B Radiation Ultraviolet Rays celecoxib chemotherapy cigarette smoking clinically significant cyclooxygenase 2 cytokine cytotoxic design environmental stressor immunoregulation improved improved outcome inhibitor/antagonist keratinocyte lipid mediator mast cell mouse model neoplastic cell novel platelet activating factor receptor pre-clinical preclinical study release factor response standard of care stressor therapy design translational study

项目摘要

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.

从化疗到紫外线，有许多环境和医源性促氧化应激源辐射已被证明可在临床前小鼠模型中诱导免疫抑制。这些压力源也被证明是脂质介质血小板激活因子（PAF）的有效诱导剂，它在小鼠模型中发挥免疫抑制作用。我们和其他团体已经描述了 PAF 依赖性免疫抑制发生的确切途径，并确定了 PAF 依赖性免疫抑制的主要作用调节性 T 细胞 (Treg)。损伤后释放的 PAF 作用于肥大细胞 PAF 受体，导致免疫抑制Tregs的形成。该过程依赖于细胞因子 IL-10 和环加氧酶-2 (COX-2) 产生前列腺素。尽管高水平的 PAF 已被证明人类对许多免疫抑制应激源产生的反应，这些应激源在动物中诱导 PAF 模型中，需要研究来确定 PAFCOX-2Treg 通路在人类中是否具有功能。此次修订 R21 应用程序旨在利用我们小组最近的发现，即局部光动力疗法 (PDT) 是小鼠皮肤中 PAF 的一种非常有效的诱导剂，并且仅在小鼠中诱导全身免疫抑制表达PAF受体。 PDT 是皮肤科中非常常见的手术，已被证明可以发挥作用对人体的免疫抑制作用。这提供了测试 PAFCOX-2Treg 通路是否存在的基本原理参与 PDT 诱导的作用，并且可以用 COX-2 抑制剂进行药理学调节以阻断免疫抑制并可能提高 PDT 治疗癌前光化性角化病的疗效病变。我们将测试在皮肤科诊所进行的标准 PDT 是否会产生：1) PAF 和相关氧化皮肤中的甘油磷酸胆碱； 2) 响应活性氧的全身异前列烷；和 3) 全身性 COX 产生的前列腺素。我们还将描述 PDT 在以下方面的免疫抑制作用：通过皮肤测试以及测定 Tregs 和 T 细胞对已建立抗原和新抗原的反应来对人类进行研究。使用 COX-2 抑制剂塞来昔布进行短期 PDT 治疗后调节 PDT 介导的能力免疫抑制和临床效果也将被定义。这些转化研究将因此定义如果 PDT 后出现了以前未被认识到的免疫调节途径，则可以利用该途径来提高治疗效果。如果成功，这些研究将改变 PDT 的护理标准管理。