ORAL EPITHELIAL CELL CYTOKINES CANDIDA & PMN ACTIVATION

口腔上皮细胞细胞因子念珠菌

• 批准号: 6380022
• 负责人: Anna I Dongari-Bagtzoglou
• 金额: $ 21.74万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380022
• 关键词: Candida albicans; candidiasis; cellular immunity; clinical research; colony stimulating factor; cytokine; gingiva; host organism interaction; human subject; interleukin 1; leukocyte activation /transformation; mixed tissue /cell culture; mucosal immunity; neutrophil; oral mucosa; pathologic process; phagocytosis; statistics /biometry

DESCRIPTION: (abstract verbatim) Oropharyngeal candidiasis is particularly prevalent in patients who are immunocompromised by disease or immunosuppressive treatment. Interestingly, even in immunocompromised patients invasive oral candidiasis is rare and seems to be associated with additional risk factors such as extreme neutropenia. One strategy for improving resistance to opportunistic pathogens is to define host cellular responses during the invasion process and enhance those responses that are relevant to defense mechanisms. Compelling experimental evidence suggests that the primary effector cell responsible for Candida clearance is the neutrophil. Neutrophils accumulate rapidly at the site of infection in the oral cavity and participate in the local control of Candida growth and invasion, yet very little is known about the host signals responsible for regulating these events. Several cytokines provide signals for neutrophil activation of antifungal functions, including interleukin-1 beta (IL-1b) and granulocyte macrophage colony stimulating factor (GM-CSF). In cases of T-helper cell depletion or inactivation, such as HIV disease or Cyclosporin A treatment, PMN are most likely potentiated in their anti-fungal function by stimulating cytokines derived from non-immune cell. Epithelial cells are capable of synthesizing IL-1b and GM-CSF and maybe one of the few defenses remaining under CD+ T cell-deficient conditions. The central hypothesis of this project is that cytokines such as IL-1b and GM-CSF are released by oral epithelial cells upon interaction with Candida and act as local stimulators of neutrophil anti-fungal functions. Using a human oral epithelial cell Candida albicans coculture model system the applicants will first determine whether this microorganism can trigger secretion of these potent neutrophil activating cytokines by oral epithelial cells. Once this goal is accomplished, mechanisms eliciting Candida-mediated cytokine responses will be explored. Finally, they will perform functional assays for these epithelial cell-derived cytokines as they relate to neutrophil activation of Candida phagocytosis and killing, using isolated neutrophils from healthy, HIV+ and Cyclosporine A-treated individuals. Given the fact that most fungal infections take place in an immunocompromised host, neutrophil priming by non-immune cell derived cytokines may be of paramount importance, not just in the initiation of a protective inflammatory response, but also in the prevention of fungal invasion into the deeper connective tissues of the oral mucosa. The studies proposed herein will be crucial in identifying oral epithelial cell-derived cytokines with the potential to prime neutrophil antifungal function in vitro. Identification of such cytokines may have future therapeutic applications in the treatment of oral candidiasis in the severely immunocompromised host.

描述：(逐字摘要)口咽念珠菌病 流行于因疾病或免疫抑制而免疫受损的患者 治疗。有趣的是，即使在免疫受损的患者中，侵入性口腔 念珠菌病很少见，似乎与其他危险因素有关。 比如严重的中性粒细胞减少症。提高抗药性的一种策略 机会性病原体是定义宿主细胞在 入侵过程，并增强与防御相关的反应 机制。令人信服的实验证据表明，主要效应器 负责清除念珠菌的细胞是中性粒细胞。中性粒细胞 在口腔感染部位迅速蓄积并参与 在局部控制假丝酵母菌的生长和入侵方面，人们知之甚少 关于负责调节这些事件的宿主信号。几个 细胞因子为中性粒细胞激活抗真菌功能提供信号， 包括白细胞介素1β(IL-1b)和粒-巨噬细胞集落 刺激因子(GM-CSF)。在T辅助细胞耗尽或 灭活，如HIV病或环孢素A治疗，中性粒细胞最多 可能通过刺激细胞因子来增强它们的抗真菌功能 来源于非免疫细胞。上皮细胞能够合成 IL-1b和GM-CSF，可能是CD+T下为数不多的防御措施之一 缺乏细胞的情况。这个项目的中心假设是 口腔上皮细胞分泌IL-1b和GM-CSF等细胞因子 与念珠菌相互作用并作为中性粒细胞抗真菌的局部刺激物 功能。人口腔上皮细胞白念珠菌共培养模型的建立 申请者将首先确定这种微生物是否可以 口服触发这些有效的中性粒细胞激活细胞因子的分泌 上皮细胞。一旦这一目标实现，机制就会引发 将探索念珠菌介导的细胞因子反应。最后，他们会 对这些上皮细胞衍生的细胞因子进行功能分析，因为它们 与中性粒细胞激活对念珠菌的吞噬和杀伤有关，应用 从健康、HIV+和环孢菌素A治疗的个体中分离出中性粒细胞。 鉴于大多数真菌感染发生在免疫功能低下的 非免疫细胞来源的细胞因子对宿主、中性粒细胞的启动可能是 最重要的是，不仅仅是在启动保护性炎症 应对措施，更是在防止真菌侵入的更深层次 口腔粘膜的结缔组织。在此建议的研究将是 在鉴定口腔上皮细胞来源的细胞因子方面具有关键作用 体外启动中性粒细胞抗真菌功能的可能性。身份识别 这类细胞因子可能在未来的治疗中有应用。 免疫功能严重受损的宿主中的口腔念珠菌病。