INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

描述（由申请人提供）：生殖器感染的义务 细胞内病原体沙眼衣原体是最常见的细菌 性传播疾病（STD）在美国，有四百万 报告的年度病例花费超过20亿美元。主要的病理生理 重要的是妇女宫颈感染的倾向， 上生殖道，引起严重的并发症，如骨盆 炎症性疾病、输卵管瘢痕形成、异位妊娠和 不孕此外，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 关注生殖器衣原体疾病，像某些其他性病，如艾滋病， 和淋球菌病，可能对人类生殖构成严重威胁， 福利和医疗费用。目前的控制和预防战略 有针对性地进行频繁筛查，以便及早发现和治疗，并制定 疫苗作为优先事项。对衣原体疫苗的研究导致了 广泛的研究来确定抗衣原体的关键免疫效应子， 免疫，鉴定引发保护性免疫的抗原，并设计 有效的疫苗接种方法。我们的研究集中在 确定衣原体免疫中的相关免疫参数， 阐明了上皮内抑制衣原体的机制。我们 其他人的发现和报告最终形成了一种新的设计模式， 基于局部粘膜TH 1诱导的抗衣原体疫苗 反应在这一阶段的主要挑战是选择一个适当的 免疫原和设计有效的递送系统，以诱导高水平的 生殖器局部黏膜Th 1应答，维持长期免疫力。因此，委员会认为， 该建议使用免疫学、基因工程、分子、细胞和 生物化学技术来研究保护性的中心假设 如果存在免疫原性衣原体感染， 有效地递送抗原以诱导高频率的特异性Th 1 生殖器粘膜中的细胞计划中的具体研究将使用基因 （a）研究基因工程小鼠和野生型小鼠的功效， 设计了由粘膜细菌组成的重组多亚单位疫苗， 共表达多个C.沙眼;（B）评估 免疫细胞疫苗的治疗益处， IL-10基因抑制的树突状细胞呈递用于诱导高表达的抗原 特异性Th 1应答的频率，作为替代治疗性疫苗， C.沙眼;（c）鉴定主要的粘膜诱导位点， 抗原呈递细胞和其他辅助细胞对Th 1活化至关重要; 和（d）确定调节Th 1活化的分子和细胞元件， 在有效的治疗后， 针对C.沙眼从这些 研究将可能导致可靠的疫苗方案的发展 对生殖器有重大影响的衣原体， 眼部和肺部感染及其并发症。

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.