CD8 Tcells and Tissue E-cadherin in Host Defense Against Oral Candidiasis in HIV

CD8 T 细胞和组织 E-钙粘蛋白在宿主防御 HIV 口腔念珠菌病中的作用

• 批准号: 8528024
• 负责人: PAUL L FIDEL
• 金额: $ 36.6万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528024
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antifungal Agents; Aspartic Endopeptidases; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; Candida; Candida albicans; Cell Adhesion Molecules; Cell Count; Cell Extracts; Cell physiology; Cells; Cellular Immunity; Clinical Research; Communicable Diseases; Defense Mechanisms; Development; Disease; E-Cadherin; Epithelial; Epithelium; Functional disorder; Fungal Drug Resistance; Goals; Growth; HIV; HIV Infections; Host Defense; Host Defense Mechanism; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Infection; Interferons; Investigation; Lamina Propria; Lesion; Link; Mediating; Modeling; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Organism; Patients; Persons; Pharmaceutical Preparations; Play; Predisposition; Protease Inhibitor; Public Health; Recruitment Activity; Research; Role; Secondary to; Site; T-Lymphocyte; Testing; Therapeutic; Tissues; Work; antiretroviral therapy; cell motility; fungus; in vitro Model; innovation; migration; novel; oropharyngeal thrush; pathogen; response; tissue culture

DESCRIPTION (provided by applicant): Oropharyngeal candidiasis (OPC) is the most common oral manifestation of HIV infection. The causative agent, Candida albicans, is both an opportunistic pathogen and common normal flora of the oral mucosa. Th1- type CD4+ cell-mediated immunity is considered the predominant host defense mechanism against OPC. However, this host response is negligible and irrelevant in HIV patients with reduced CD4+ T cell numbers. Instead other secondary host defenses against C. albicans are required under reduced CD4+ T cell conditions. The elucidation of oral anti-Candida immune defense mechanisms that can effectively operate in the absence of adequate numbers of CD4+ T cells is crucial for the development of novel immunotherapies that will enhance protective immune responses to OPC in HIV+ individuals. Accordingly, our studies have implicated CD8+ T cells as playing a putative 'secondary' role in host defense against OPC. In this role, CD8+ effector T cells are recruited into the oral mucosa and migrate throughout the lamina propria and epithelium, providing effector function where necessary. In OPC, however, they accumulate at the basolateral epithelial/lamina propria interface and correlates with a reduction in epithelial expression of the adhesion molecule, E-cadherin, which facilitates migration of CD8+ T cells in the epithelium. We hypothesize that CD8+ T cells have anti- Candida activity in the oral cavity, but optimal effector function is often precluded by Candida-mediated aberrations of tissue E-cadherin that can be reversed/restored therapeutically. Hence this project will focus on the uncharacterized anti-Candida host defense mechanisms by CD8+ T cells in the oral cavity, that we believe may be a novel immune mechanism and influenced by both the organism and components of antiretroviral or immuno therapies. Following completion of the project we expect to demonstrate how these 'secondary' type of immune responses function against Candida in the oral cavity, how and why they can be ineffective, and how existing antiretroviral and immune therapies not only link to these 'secondary' responses, but also how they can be exploited further to control OPC in HIV disease.

描述（由申请人提供）：口咽念珠菌病（OPC）是艾滋病毒感染的最常见口服表现。病因念珠菌白色念珠菌既是口服粘膜的机会性病原体，也是常见的正常植物。 Th1-型CD4+细胞介导的免疫被认为是针对OPC的主要宿主防御机制。但是，这种宿主反应可忽略不计，而与CD4+ T细胞数量降低的HIV患者无关。相反，在降低的CD4+ T细胞条件下需要针对白色念珠菌的其他次要宿主防御。在没有足够数量的CD4+ T细胞的情况下，可以有效起作用的口服抗Candida免疫防御机制，对于开发新型免疫疗法至关重要，这将增强对HIV+个体OPC的保护性免疫反应。因此，我们的研究已将CD8+ T细胞视为在针对OPC的宿主防御中扮演“次要”角色。在此角色中，CD8+效应T细胞被募集到口服粘膜中，并在整个固有椎板和上皮中迁移，并在必要时提供效应功能。然而，在OPC中，它们积聚在基底外侧/薄片膜片界面上，并与粘附分子E-钙粘蛋白的上皮表达降低相关，这促进了上皮细胞中CD8+ T细胞的迁移。我们假设CD8+ T细胞在口腔中具有抗念珠菌活性，但是最佳效应子功能通常被念珠菌介导的组织E-钙粘着蛋白的畸变所阻止，可以通过治疗逆转/恢复。因此，该项目将集中于口腔中CD8+ T细胞的未表征的抗Candida宿主防御机制，我们认为这可能是一种新型的免疫机制，并受抗逆转录病毒或免疫疗法的生物和成分的影响。项目完成后，我们期望证明这些“次要”类型的免疫反应如何针对口腔中的念珠菌，如何以及为什么无效，以及现有的抗逆转录病毒和免疫疗法如何与这些“次要”反应联系起来，还可以进一步利用它们，以进一步利用它们。