ORAL EPITHELIAL CELL CYTOKINES--CANDIDA & PMN ACTIVATION

描述：（逐字摘要）口咽念珠菌病特别是 在因疾病或免疫抑制而免疫功能低下的患者中普遍存在 治疗有趣的是，即使在免疫功能低下的患者中， 念珠菌病是罕见的，似乎与其他危险因素有关 例如极端中性粒细胞减少症。一种提高对 机会致病菌是定义宿主细胞反应期间， 入侵过程和增强那些与防御相关的反应 机制等令人信服的实验证据表明， 负责念珠菌清除的细胞是中性粒细胞。中性粒 在口腔感染部位迅速积聚， 在局部控制念珠菌的生长和侵袭，但知之甚少 关于负责调节这些事件的宿主信号。几 细胞因子为嗜中性粒细胞激活抗真菌功能提供信号， 包括白细胞介素-1 β（IL-1b）和粒细胞巨噬细胞集落 刺激因子（GM-CSF）。在T辅助细胞耗竭的情况下， 灭活，如HIV疾病或环孢菌素A治疗，PMN是最 可能通过刺激细胞因子增强其抗真菌功能 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下剩下的少数防御之一 细胞缺乏的条件。这个项目的核心假设是， 细胞因子如IL-1b和GM-CSF由口腔上皮细胞释放， 与念珠菌相互作用并作为中性粒细胞抗真菌局部刺激物 功能协调发展的采用人口腔上皮细胞白念珠菌共培养模型 系统中，申请人将首先确定该微生物是否可以 通过口服，触发这些有效的中性粒细胞激活细胞因子的分泌 上皮细胞一旦实现这一目标， 将探索曲马多介导的细胞因子应答。最后，他们会 对这些上皮细胞衍生的细胞因子进行功能测定， 涉及中性粒细胞激活念珠菌的吞噬和杀伤作用， 从健康、HIV+和环孢霉素A治疗的个体分离的中性粒细胞。 鉴于大多数真菌感染发生在免疫功能低下的 在宿主中，由非免疫细胞衍生的细胞因子引起的嗜中性粒细胞引发可能是 最重要的是，不仅仅是在启动一个保护性的炎症， 反应，而且在预防真菌入侵到更深 口腔粘膜的结缔组织。本文提出的研究将 在确定口腔上皮细胞衍生的细胞因子与 体外激发中性粒细胞抗真菌功能的潜力。鉴定 这种细胞因子在治疗以下疾病中具有未来的治疗应用 严重免疫缺陷宿主的口腔念珠菌病。

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.