INDUCTION OF DELAYED HYPERSENSITIVITY TO SIV

对 SIV 迟发性超敏反应的诱导

• 批准号: 2424595
• 负责人: Michael B. McChesney
• 金额: $ 5.95万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2424595
• 关键词: AIDS vaccines; Macaca mulatta; T lymphocyte; active immunization; antibody formation; delayed hypersensitivity; dendritic cells; leukocyte activation /transformation; macrophage; microorganism immunology; mucosal immunity; neutralizing antibody; simian AIDSs; simian immunodeficiency virus; tissue /cell culture; vaccine development; virus antigen

The development of a safe and effective HIV vaccine is a formidable task. Both antibody and cytotoxic T cell responses to HIV are generated during the infection, but these responses cannot ultimately control the infection or prevent progression to fatal immunodeficiency in the majority of infected individuals. This suggests that there is a reservoir of infected cells that are not recognized or eliminated by these two classical antiviral immune mechanisms. We hypothesize that a novel immune response, one that is not induced during the natural infection, could be effective as a vaccine - induced immune mechanism, giving the vaccinated host an additional antiviral effector mechanism prior to exposure to HIV. This candidate immune response, delayed type hypersensitivity (DTH), is a key controlling immune response in other viral and intracellular bacterial infections, particularly in human infections with tuberculosis and leprosy. Using the SIV/macaque animal model of HIV infection and AIDS, the goal of this small research grant proposal is to induce a DTH response to SIV antigens in rhesus monkeys. SIv antigen-pulsed dendritic cells will be used to direct the effector response toward DTH. An in vitro culture system will be developed to model the DTH response as the control of productive SIV infection in rhesus monocyte/macrophage by autologous, immune T cells. If antigen specific and MHC-restricted responses are detected in immunized animals, they will be challenged by mucosal inoculation of pathogenic SIVmac251. The outcome of challenge will be assessed by quantitative viral load measurements, antiviral immune responses and pathologicchanges in tissues. If antiviral DTH is a protective immune response to SIV, significant reduction in viral load during the acute stage of infection, enhanced DTH and CTL responses and a delayed neutralizing antibody response are expected. In addition, the pathologic changes of disseminated SIV infection in peripheral lymphoid tissues should be significantly reduced. These outcomes would support the concept of antiviral DTH as a protective immune response to target with a novel HIV vaccine.

开发安全有效的艾滋病毒疫苗是一项 艰巨的任务抗体和细胞毒性T细胞对 艾滋病毒在感染过程中产生，但这些反应不能 最终控制感染或防止进展到致命的 大多数感染者的免疫缺陷。这 表明有一个受感染的细胞库， 识别或消除这两个经典的抗病毒免疫 机制等我们假设一种新的免疫反应， 在自然感染过程中不会被诱导， 作为疫苗诱导的免疫机制， 在暴露前宿主额外的抗病毒效应机制 艾滋病毒。这种候选免疫反应，延迟型 超敏反应（DTH）是控制免疫反应的关键， 其他病毒和细胞内细菌感染，特别是在 人类感染结核病和麻风病。使用 SIV/猕猴动物模型HIV感染与艾滋病的目标 这项小型研究拨款建议的目的， 猴免疫缺陷病毒抗原。SIv抗原致敏树突状细胞 细胞将用于引导效应子应答朝向DTH。一个 将建立一个体外培养系统来模拟DTH 反应作为恒河猴生产性SIV感染的控制 单核细胞/巨噬细胞通过自体免疫T细胞。If抗原 在免疫的小鼠中检测到特异性和MHC限制性应答， 动物，将通过粘膜接种 致病性SIVmac 251。将评估挑战结果 通过定量病毒载量测量，抗病毒免疫 组织的反应和病理变化。如果抗病毒DTH是一种 对SIV的保护性免疫反应， 感染急性期负荷，DTH和CTL增强 中和抗体应答和延迟中和抗体应答， 预期此外，播散性SIV的病理变化 外周淋巴组织中的感染应显著 降低这些结果将支持抗病毒的概念 DTH作为一种新型HIV靶向保护性免疫应答 疫苗