Oral Immune Dysfunction and Candidiasis in HIV Infection

描述（由申请人提供）： 口咽念珠菌病（OPC）仍然是最常见的艾滋病毒感染的口腔表现。虽然已经取得了相当大的进展，以确定发生在口腔粘膜的免疫事件，防止或有助于临床OPC的发展，潜在的机制或耐药和敏感性OPC仍然知之甚少。临床和实验室研究表明，由CD 4 + T细胞和相关细胞因子介导的Th 1型细胞免疫是宿主抵抗口腔念珠菌的主要防御机制。白色念珠菌感染我们过去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CD 4细胞数量减少的患者中，但没有证据表明外周血淋巴细胞的血小板特异性反应功能障碍。相反，似乎存在保护口腔免受OPC所需的CD 4 + T细胞的阈值数量，低于该阈值，局部粘膜机制变得越来越重要。因此，在CD 4细胞减少期间对OPC的易感性与唾液中占优势的Th 2型细胞因子谱、CD 8 + T细胞的积累（其似乎被限制运输到外部上皮的浅表感染部位）以及口腔上皮细胞抑制C.白色念珠菌因此，我们假设，CD 8 + T细胞和相关的细胞因子/趋化因子，连同上皮细胞，代表重要的口腔宿主防御机制时，CD 4 + T细胞下降到保护水平以下，在一个或多个这些防御功能障碍有助于OPC的发作。为了验证这一假设，我们将继续关注我们在路易斯安那州立大学健康科学中心的HIV门诊项目中有和没有OPC的大型城市人群，并1）评估有和没有OPC的HIV+人群口腔组织中CD 8 + T细胞的免疫状态（纵向评价，粘附分子，活化/共刺激），2）评估口腔组织中CD 8 + T细胞相关的细胞因子/趋化因子（蛋白质和mRNA），和3）鉴定功能部分并表征口腔上皮细胞抗念珠菌活性的活性和机制。该项目的长期目标是确定与HIV+个体对OPC易感性相关的特异性免疫因素，并制定免疫策略，以在CD 4 + T细胞减少期间增强对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.