TARGETED DELIVERY OF ANTIGENS TO INDUCE HIV IMMUNITY

定向递送抗原以诱导 HIV 免疫

• 批准号: 6313448
• 负责人: M ABDUL JABBAR
• 金额: $ 24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6313448
• 关键词: AIDS vaccines; CD28 molecule; CD40 molecule; HIV envelope protein; MHC class I antigen; Macaca mulatta; T cell receptor; T lymphocyte; antigen presentation; antigen presenting cell; cellular immunity; chimeric proteins; fusion gene; humoral immunity; interferon gamma; laboratory mouse; receptor binding; surface antigens; vaccine development; vector vaccine

DESCRIPTION: (Adapted from Applicant's Abstract) B and T-lymphocytes, the effector arms of the immune system, traffic through the secondary lymphoid organs (lymph nodes, Peyers' patches, etc.) and peripheral tissues to sample the body for the presence of pathogens. B cells bind native proteins through specific cell surface receptors (BCR) for antigen presentation, whereas T cells (CD4+ and CD8+) rely on the remarkable ability of antigen presenting cells (APCs) to ferry antigens to their close proximity in the lymph node or spleen. This process of selective trafficking by cells of the immune system is critical to induce appropriate immune responses that would have the ability to impose immune containment of the pathogens. The strength of the primary immune response critically determines the level and duration of recall memory responses to the same antigen. The goal of vaccination is to induce immunological memory that persists for the life of the host. The DNA vaccine-induced expression of antigens is often inadequate to efficiently prime T cells. Under these conditions, a second signal in the form of co-stimulation involving cell surface proteins on APCs (B7 proteins, CD40) and T cells (CD28, CTLA4, and CD40L) is required for full activation of T cells. We tap into this particular ability of APCs to prime T cells, which would have the ability to efficiently induce HIV envelope-specific immune responses. HIV envelope is poorly immunogenic in various animal species (mice, macaques, and humans). One major reason being that the heavily glycosylated HIV envelope may not be easily accessible to the antigen presentation pathways of APCs. In the current proposal, we have devised a strategy in which HIV antigens could be targeted directly to APCs. The specific aims are: 1) Construction and expression of the envelope genes (gp120 and gp140) genetically linked to those coding for the T cell ligands, CTLA4 and CD40L. 2) Genetic immunization of mice with the gene fusion constructs and analysis of vaccine-induced immune responses (e.g., CTL assay, intracellular gamma INF production, tetramer stain, ELISPOT assay). 3) Testing of prospective candidate DNA vaccines for their ability to induce immune responses in rhesus macaques. Effective priming of T cells by both TCR engagement and targeted delivery of antigens via co-stimulatory molecules would have the potential to expand T cells that are critical for establishment and maintenance of immunological memory. The success of this novel vaccine approach will have major implications in the development of DNA vaccines having the ability to induce effective B and T cell responses in animals.

描述：（改编自申请人的摘要）B和T淋巴细胞， 免疫系统的效应臂，通过次级淋巴管的交通 器官（淋巴结，Peyers的斑块等）和外周组织 病原体存在的身体。 B细胞通过 用于抗原表现的特定细胞表面受体（BCR），而T细胞 （CD4+和CD8+）依赖于抗原呈递细胞的显着能力 （APC）将抗原转移到淋巴结或脾脏中的近端。 免疫系统细胞的选择性运输过程至关重要 诱发适当的免疫反应，有能力 病原体的免疫遏制。初级免疫的强度 响应批判性地确定召回记忆的水平和持续时间 对同一抗原的反应。疫苗接种的目的是诱导 免疫记忆持续到宿主的生命。 DNA 疫苗诱导的抗原表达通常不足以有效质量 T细胞。在这些条件下，以共刺激形式的第二个信号 涉及APC（B7蛋白，CD40）和T细胞（CD28，CD28， CTLA4和CD40L）是完全激活T细胞所必需的。我们利用这一点 APC启用T细胞的特殊能力，这将具有能力 有效诱导HIV特异性免疫反应。 HIV信封是 各种动物种类（小鼠，猕猴和人类）的免疫原性不良。一 主要原因是大量糖基化的HIV信封可能不容易 可以访问APC的抗原表现途径。在电流中 提案，我们制定了一种可以针对艾滋病毒抗原的策略 直接到APC。具体目的是：1） 包膜基因（GP120和GP140）遗传与编码T 细胞配体CTLA4和CD40L。 2）用基因对小鼠的遗传免疫 疫苗诱导的免疫反应的融合构建体和分析（例如CTL 测定，细胞内伽马INF产生，四聚体染色，ELISPOT测定）。 3） 测试预期候选DNA疫苗的诱导能力 恒河猕猴中的免疫反应。两个TCR有效启动T细胞 通过共同刺激分子的参与和针对抗原的目标递送将 有可能扩大对建立至关重要的T细胞 免疫记忆的维护。这种新型疫苗方法的成功 将对具有的DNA疫苗的开发产生重大影响 能够在动物中诱导有效的B和T细胞反应。