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HIV感染最常见的口腔表现。病原体白色念珠菌既是一种条件致病菌，也是口腔粘膜常见的正常植物群。Th 1型CD 4+细胞介导的免疫被认为是宿主对OPC的主要防御机制。然而，这种宿主反应对于CD 4 + T细胞数量减少的HIV患者来说可以忽略不计且无关紧要。相反，其他次要宿主对C。在CD 4 + T细胞减少的条件下需要白色念珠菌。阐明口服抗念珠菌免疫防御机制，可以有效地运作，在没有足够数量的CD 4 + T细胞是至关重要的新的免疫疗法，将增强保护性免疫反应OPC在HIV+个人的发展。因此，我们的研究表明，CD 8 + T细胞在宿主防御OPC中起着假定的“次要”作用。在这个角色中，CD 8+效应T细胞被招募到口腔粘膜中，并在整个固有层和上皮中迁移，在必要时提供效应功能。然而，在OPC中，它们在基底外侧上皮/固有层界面处积累，并且与粘附分子E-钙粘蛋白的上皮表达减少相关，所述粘附分子E-钙粘蛋白促进上皮中的CD 8 + T细胞的迁移。我们假设CD 8 + T细胞在口腔中具有抗念珠菌活性，但最佳效应子功能通常被念珠菌介导的组织E-钙粘蛋白的畸变排除，所述畸变可以在治疗上逆转/恢复。因此，该项目将重点关注口腔中CD 8 + T细胞的未表征的抗念珠菌宿主防御机制，我们认为这可能是一种新的免疫机制，并受到抗逆转录病毒或免疫疗法的生物体和组分的影响。该项目完成后，我们希望展示这些“次级”类型的免疫反应如何在口腔中对抗念珠菌，它们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不仅与这些“次级”反应有关，而且如何进一步利用它们来控制艾滋病中的OPC。