Oral Immune Dysfunction and Candidiasis in HIV Infection

描述(由申请人提供)： 口咽念珠菌病(OPC)仍然是HIV感染最常见的口腔表现。虽然在确定口腔粘膜发生的免疫事件以预防或促进临床OPC的发展方面已经取得了相当大的进展，但OPC的潜在机制或耐药性和易感性仍然知之甚少。临床和实验室研究表明，由CD4+T细胞及相关细胞因子介导的Th1型细胞免疫是口腔白念珠菌感染的主要宿主防御机制。我们过去5年的数据支持这一点，但也增加了相当大的复杂性。虽然OPC主要发生在CD4细胞数量减少的患者中，但没有证据表明外周血淋巴细胞对念珠菌的特异性反应功能障碍。相反，似乎有一个阈值数量的CD4+T细胞，以保护口腔免受OPC，低于这个阈值的局部粘膜机制变得越来越关键。因此，在CD4细胞减少的情况下对OPC的易感性与唾液中主要的Th2型细胞因子分布、CD8+T细胞的聚集(似乎限制了CD8+T细胞向外上皮表面感染部位的运输)以及口腔上皮细胞抑制白色念珠菌生长的能力降低有关。因此，我们假设CD8+T细胞和相关的细胞因子/趋化因子与上皮细胞一起，代表着重要的口服宿主防御机制，当CD4+T细胞降至保护水平以下时，其中一个或多个防御系统的功能障碍导致OPC的发生。为了验证这一假设，我们将继续关注路易斯安那州立大学健康科学中心HIV门诊计划中患有OPC和没有OPC的大量城市队列，1)评估HIV+OPC患者和没有OPC患者口腔组织中CD8+T细胞的免疫状态(纵向评估、黏附分子、激活/共刺激)，2)评估口腔组织中CD8+T细胞相关的细胞因子/趋化因子(蛋白质和mRNA)，以及3)确定口腔上皮细胞抗念珠菌活性的功能部分并表征其活性和机制。该项目的长期目标是确定与HIV+患者OPC易感性相关的特定免疫因素，并开发免疫治疗策略，以增强在CD4+T细胞减少期间对OPC的抵抗力。

DESCRIPTION (provided by applicant): Oropharyngeal candidiasis (OPC) remains the most common oral manifestation of HIV infection. Although considerable progress has been made toward identifying the immunological events taking place at the oral mucosa that protects against, or contributes to, the development of clinical OPC, the underlying mechanisms or resistance and susceptibility to OPC remain poorly understood. Clinical and laboratory investigations suggest that Th1-type cell-mediated immunity by CD4+ T cells and related cytokines is the predominant host defense mechanism against oral C. albicans infection. Our data over the past 5 years supports this, but also adds considerable complexity. While OPC primarily occurs in those with reduced CD4 cell numbers, there is no evidence for a dysfunction in Candida-specific responsiveness by peripheral blood lymphocytes. Instead there appears to be a threshold number of CD4+ T cells required to protect the oral cavity against OPC, below which local mucosal mechanisms become increasingly critical. Accordingly, susceptibility to OPC during reduced CD4 cells correlates with a predominant Th2-type cytokine profile in saliva, an accumulation of CD8+ T cells that appear restricted from trafficking to the site of the superficial infection at the outer epithelium, and a reduced capacity for oral epithelial cells to inhibit the growth of C. albicans. Therefore, we hypothesize that CD8+ T cells and related cytokines/chemokines, together with epithelial cells, represent important oral host defense mechanisms when CD4+ T cells drop below protective levels and that dysfunctions in one or more of these defenses contribute to episodes of OPC. To test this hypothesis we w continue to focus on our large urban cohort of individuals with and without OPC in the HIV Outpatient Program at LSU Health Sciences Center and 1) evaluate the immune status of CD8+ T cells in oral tissue o HIV+ persons with and without OPC (longitudinal evaluation, adhesion molecules, activation/costimulation), 2) evaluate CD8+ T cell-associated cytokines/chemokines in oral tissues (protein and mRNA), and 3) identify the functional moiety and characterize the activity and mechanism of oral epithelial cell anti-Candida activity. The long-term goals of the project are to identify the specific immune factors associated with the susceptibility to OPC in HIV+ individuals, and to develop immunotherapeutic strategies to enhance resistance against OPC during periods of reduced CD4+ T cells.