INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

诱导针对衣原体的保护性免疫力

• 批准号: 6331908
• 负责人: Francis O. Eko
• 金额: $ 32.83万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6331908
• 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）：义务人的生殖器感染 细胞内病原体沙眼衣原体是最常见的细菌 在美国，有 400 万人患有性传播疾病 (STD) 每年报告的案件花费超过 20 亿美元。主要病理生理学 重要的是女性宫颈感染传播到其他地方的倾向 上生殖道，引发严重的并发症，例如盆腔 炎症性疾病、输卵管疤痕、宫外孕和 不孕症。此外，频繁的无症状感染确实会导致严重的 不可逆的并发症是感染的第一个证据。有 担心生殖器衣原体疾病，就像某些其他性传播疾病，例如艾滋病 和淋菌病，可能对人类生殖构成严重威胁， 福祉和医疗保健费用。当前的控制和预防策略 以频繁筛查为目标，以实现早期发现和治疗，并开发 疫苗为优先。对衣原体疫苗的研究导致 广泛的研究来确定抗衣原体中关键的免疫效应子 免疫，识别引发保护性免疫的抗原，并设计 有效的疫苗接种方法。我们的研究一直集中在 识别衣原体免疫中的相关免疫参数和 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最终形成了一种新的设计范式 基于局部粘膜 TH1 诱导的衣原体疫苗 回复。这个阶段的主要挑战是选择合适的 免疫原并设计有效的递送系统，以诱导高水平的免疫原 生殖器局部粘膜的Th1反应可维持长期免疫力。因此， 该提案使用了免疫学、基因工程、分子、细胞和 生化技术来研究保护性的中心假设 如果衣原体具有免疫原性，则将建立抗衣原体免疫力 有效递送抗原以诱导高频率的特定 Th1 生殖器粘膜中的细胞。计划的具体研究将使用基因 工程小鼠和野生型小鼠：(a) 研究基因的功效 设计了由粘膜细菌组成的重组多亚单位疫苗 共表达沙眼衣原体多种膜蛋白的鬼影； (b) 评估 基于免疫治疗细胞疫苗的治疗益处 IL-10基因抑制的树突状细胞呈递抗原以诱导高 特定 Th1 反应的频率，作为替代治疗疫苗 沙眼衣原体； (c) 确定主要的粘膜感应位点， 抗原呈递细胞和其他对 Th1 激活至关重要的辅助细胞； (d) 定义调节 Th1 激活的分子和细胞元件， 有效后贩运和募集到生殖器粘膜 针对沙眼衣原体的细胞和亚单位疫苗接种。这些结果 研究可能会导致开发出可靠的疫苗方案 对抗衣原体，这应该对生殖器产生重大影响， 眼部和肺部感染及其并发症。