INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

诱导针对衣原体的保护性免疫力

• 批准号: 6891300
• 负责人: Francis O. Eko
• 金额: $ 41.91万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891300
• 关键词: Chlamydia trachomatis; bacterial vaccines; bactericidal immunity; cell migration; cellular immunity; chlamydial disease; dendritic cells; genetically modified animals; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; mucosal immunity; reproductive system disorder; vaccine development

DESCRIPTION (provided by the applicant): Genital infection by the obligate intracellular pathogen, Chlamydia trachomatis, is the most common bacterial sexually transmitted disease (STD) in the United States, with four million reported annual cases that cost over $2 billion. Of major pathophysiological significance is the propensity for cervical infection in women to spread into the upper genital tract, provoking serious complications such as pelvic inflammatory disease, fallopian tube scarring, ectopic pregnancy and infertility. Also, the frequently asymptomatic infections do cause severe irreversible complications to be the first evidence of an infection. There are concerns that genital chlamydial disease, like certain other STDs, such as AIDS and gonococcal disease, may pose a serious threat to human reproduction, well-being and healthcare costs. Current control and prevention strategies target frequent screening for early detection and treatment, and development of vaccines as the priority. The search for a chlamydial vaccine has led to extensive research to define the crucial immune effectors in anti-chlamydial immunity, identify antigens that elicit protective immunity, and design effective methods of vaccine delivery. Our research has been focused on identifying the relevant immune parameters in chlamydial immunity and elucidating the mechanism(s) of intraepithelial inhibition of chlamydiae. Our findings and reports by others have culminated in a new paradigm for designing vaccines against Chlamydia based on the induction of local mucosal TH1 response. The major challenge at this stage is to select an appropriate immunogen(s) and design an effective delivery system, to induce high levels of local genital mucosal Th1 response to maintain long-term immunity. Accordingly, this proposal uses immunological, genetic engineering, molecular, cellular and biochemical techniques to investigate the central hypothesis that protective anti-chlamydial immunity will be established if immunogenic chlamydial antigen(s) are effectively delivered to induce high frequency of specific Th1 cells in the genital mucosa. Specific studies planned will use genetically engineered and wild type mice to: (a) investigate the efficacy of genetically designed recombinant multi-subunit vaccines composed of mucosal bacterial ghosts co-expressing multiple membrane proteins of C. trachomatis; (b) assess the therapeutic benefits of an immunotherapeutic cellular vaccine based on IL-lO gene-suppressed dendritic cells presenting antigens for inducing high frequency of specific Th1 response, as an alternative therapeutic vaccine for C. trachomatis; (c) identify the major mucosal inductive sites, antigen-presenting cells and other accessory cells crucial for Th1 activation; and (d) define the molecular and cellular elements regulating Th1 activation, trafficking and recruitment into the genital mucosa following effective cellular and subunit vaccination against C. trachomatis. Results from these studies will likely lead to the development of a reliable vaccine regimen against Chlamydia, which should have major implications for the genital, ocular, and lung infections and their complications.

描述（由申请人提供）：强制性的生殖器感染 细胞内病原体，沙眼衣原体，是最常见的细菌 美国的性传播疾病（STD），有四百万 报告的年案件耗资超过20亿美元。主要的病理生理学 显着性是女性宫颈感染倾向扩散到 上生殖道，引起严重的并发症，例如骨盆 炎症性疾病，输卵管疤痕，异位妊娠和 不育。而且，经常无症状的感染确实会导致严重 不可逆转的并发症是感染的第一个证据。有 担心与某些其他性传播疾病一样，生殖器衣原体疾病，例如艾滋病 和淋球菌疾病可能对人类繁殖构成严重威胁， 福祉和医疗保健费用。当前的控制和预防策略 目标频繁筛查以进行早期检测和治疗，并开发 疫苗作为优先级。寻找衣原体疫苗已导致 广泛的研究，以定义抗卫生的关键免疫效应子 免疫，确定引起保护性免疫的抗原并设计 疫苗输送的有效方法。我们的研究集中在 确定衣原体免疫中相关的免疫参数和 阐明衣原体上皮内抑制的机制。我们的 其他人的发现和报告已达到设计的新范式 基于诱导局部粘膜Th1的疫苗针对衣原体 回复。此阶段的主要挑战是选择适当的 免疫原并设计有效的输送系统，以诱导高水平 局部生殖器粘膜Th1反应以维持长期免疫力。因此， 该建议使用免疫学，基因工程，分子，细胞和 生化技术来研究保护性的中心假设 如果免疫原性，将建立抗神经免疫力 抗原有效地递送以诱导特定Th1的高频 生殖器粘膜中的细胞。计划的特定研究将在基因上使用 工程和野生型小鼠至：（a）研究遗传学的功效 设计的重组多物质疫苗由粘膜细菌组成 幽灵共表达梭状芽孢杆菌的多种膜蛋白； （b）评估 基于免疫治疗性细胞疫苗的治疗益处 IL-LO基因抑制的树突状细胞呈现抗原，以诱导高 特定Th1反应的频率，作为一种替代治疗疫苗 C.气头菌； （c）确定主要的粘膜诱导部位， 抗原呈递细胞和其他辅助细胞对于Th1激活至关重要； （d）定义调节Th1激活的分子和细胞元素， 有效后，贩运和招募到生殖器粘膜 针对沙眼霉菌的细胞和亚基疫苗接种。这些结果 研究可能会导致可靠的疫苗方案的发展 反对衣原体，这应该对生殖器有重大影响， 眼，肺部感染及其并发症。