Regulation of Mucosal Immunity by Pro- and Anti-inflammatory Salivary Defensins

促炎和抗炎唾液防御素对粘膜免疫的调节

• 批准号: 8127613
• 负责人: MICHAEL E SELSTED
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-12 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127613
• 关键词: Adult; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Bacterial Antigens; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Clinical; Defensins; Dendritic Cells; Elements; Epithelial Cells; Exposure to; HIV; HIV Infections; HIV vaccine; Host Defense; Human; Immune response; Immunity; Immunologics; Individual; Infection; Laboratories; Macaca; Macaca mulatta; Mucosal Immunity; Natural Immunity; Oral; Oral cavity; Oral mucous membrane structure; Patients; Peptides; Physiological; Primates; Property; Proteins; Regulation; Resistance; Role; SIV; Saliva; Salivary; Signal Transduction; T-Lymphocyte; adaptive immunity; design; immunoregulation; insight; macrophage; microbial; monocyte; nonhuman primate; oral HIV; oral cavity epithelium; pathogen; pre-clinical; public health relevance; response; vaccine development

DESCRIPTION (provided by applicant): The long term objective of this project is to determine the properties of saliva that endow the oral cavity with unique resistance and immunologic responsiveness to HIV. Previous studies have demonstrated that defensins, host defense peptides involved in innate immunity, are capable of directly inhibiting HIV infection of susceptible target cells. In addition, defensins are known to activate elements of innate and adaptive immunity (T-cells, monocytes, macrophages, dendritic cells), thus providing signals essential for the acquisition of humoral and/or cell-mediated immunity against a variety of microbial pathogens. Defensins are produced in saliva of humans and non-human primates. This project seeks to characterize the role of salivary defensins in regulating immune responses in the oral cavity of rhesus macaques, a primate with a clinical response to SIV infection that is quite similar to that observed in human HIV infection. Recent studies in the PI's laboratory have demonstrated that, in addition to direct anti-HIV activity of defensin subclasses, these peptides also have profound immunomodulatory activities. We hypothesize that immunoregulation by salivary defensins establishes a unique immunologic milieu in oral mucosa that determines the early response of the host to HIV exposure. An understanding of the interactions between defensins and cellular elements of the oral mucosa will provide insights into the network of interactions that determine the immune responses to SIV in the oral cavity. To achieve these objectives, we propose the following Specific Aims: 1) Quantify the a, ¿, and ?-defensin content in whole saliva of healthy and chronically SIV-infected macaques; 2) determine the anti-SIV activity of physiologic concentrations of individual and combined peptides in the presence or absence of defensindepleted whole saliva; 3) determine the effect of individual and combined salivary defensins on the activation profile of PBMCs, monocytes, monocyte-derived macrophages, monocyte-derived dendritic cells, and CD4+ lymphocytes; and 4) Evaluate the effect of salivary defensins on the infectivity of HIV of oral epithelial cells, the response of oral epithelium to bacterial antigens, and the transport of HIV from the epithelial cells to permissive CD4+ target cells. Taken together, these studies will provide new insights into the unique features of immunity in the oral cavity of rhesus monkeys, thereby guiding preclinical approaches to SIV and HIV vaccine development. PUBLIC HEALTH RELEVANCE: Oral exposure to HIV rarely results in infection in adults. Moreover, antibodies present in the saliva of patients who have been exposed to HIV but who remain uninfected, appear to be protective. This project seeks to understand how small proteins (defensins) produced in saliva influence the resistance of the oral cavity to HIV infection, and how they may be useful in the design of anti-HIV vaccines.

描述（由申请人提供）：该项目的长期目标是确定赋予口腔对HIV的独特抵抗力和免疫反应性的唾液特性。以往的研究表明，防御素，参与先天免疫的宿主防御肽，能够直接抑制易感靶细胞的HIV感染。此外，已知防御素激活先天性和适应性免疫的元件（T细胞、单核细胞、巨噬细胞、树突细胞），从而提供获得针对多种微生物病原体的体液和/或细胞介导的免疫所必需的信号。 防御素在人类和非人类灵长类动物的唾液中产生。该项目旨在描述唾液防御素在调节恒河猴口腔免疫反应中的作用，恒河猴是一种对SIV感染具有临床反应的灵长类动物，与在人类HIV感染中观察到的非常相似。PI实验室最近的研究表明，除了防御素亚类的直接抗HIV活性外，这些肽还具有深刻的免疫调节活性。我们推测唾液防御素的免疫调节作用在口腔粘膜中建立了一个独特的免疫环境，决定了宿主对HIV暴露的早期反应。防御素和口腔粘膜细胞成分之间的相互作用的理解将提供深入了解网络的相互作用，决定在口腔SIV的免疫反应。为了实现这些目标，我们提出了以下具体目标：1）量化a，<$，和？健康和慢性SIV感染的猕猴的全唾液中的防御素含量; 2）在防御素缺失的全唾液存在或不存在的情况下测定生理浓度的单独和组合的肽的抗SIV活性; 3）测定单独和组合的唾液防御素对PBMC、单核细胞、单核细胞衍生的巨噬细胞、单核细胞衍生的树突细胞和CD 4+淋巴细胞的活化谱的影响;（4）评价唾液防御素对口腔上皮细胞的HIV感染性、口腔上皮对细菌抗原的应答以及HIV从上皮细胞转运到容许的CD 4+靶细胞的作用。总而言之，这些研究将为恒河猴口腔免疫的独特特征提供新的见解，从而指导SIV和HIV疫苗开发的临床前方法。 公共卫生相关性：口服暴露于HIV很少导致成人感染。此外，暴露于艾滋病毒但未感染的患者唾液中存在的抗体似乎具有保护作用。该项目旨在了解唾液中产生的小蛋白（防御素）如何影响口腔对艾滋病毒感染的抵抗力，以及它们如何在抗艾滋病毒疫苗的设计中发挥作用。