INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

描述(由申请人提供)：义务人生殖器感染 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400万人 每年报告的病例花费超过20亿美元。主要的病理生理学 重要的是妇女的宫颈感染有扩散到 上生殖道，引起严重的并发症，如骨盆 炎症性疾病、输卵管疤痕、异位妊娠和 不孕不育。此外，频繁的无症状感染确实会导致严重的 不可逆转的并发症是感染的第一个证据。确实有 令人关切的是，生殖器衣原体疾病与艾滋病等其他性传播疾病一样 和淋球菌疾病，可能对人类生殖构成严重威胁， 福利和医疗保健成本。当前的控制和预防战略 针对早期发现和治疗的目标频繁筛查，以及发展 疫苗是当务之急。对衣原体疫苗的研究导致了 广泛研究以确定抗衣原体的关键免疫效应物 免疫，识别引起保护性免疫的抗原，并设计 有效的疫苗接种方法。我们的研究一直集中在 确定衣原体免疫中的相关免疫参数 阐明衣原体上皮内抑制的机制(S)。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 回应。现阶段的主要挑战是选择合适的 免疫基因(S)并设计了有效的递送系统，以诱导高水平的 局部生殖器粘膜Th1反应，维持长期免疫。因此， 这一提议使用了免疫学、遗传工程、分子、细胞和 生物化学技术研究保护作用的中心假说 如果免疫原性衣原体，将建立抗衣原体免疫 有效递送S抗原诱导高频率特异性Th1 生殖器粘膜中的细胞。计划中的特定研究将使用基因 转基因和野生型小鼠：(A)研究基因治疗的效果 设计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幽灵；(B)评估 免疫治疗性细胞疫苗的治疗效果 IL-LO基因抑制树突状细胞提呈抗原诱导高表达 特异性Th1应答的频率，作为一种替代治疗疫苗 沙眼衣原体；(C)确定主要的粘膜诱导部位， 抗原提呈细胞和其他对Th1激活至关重要的辅助细胞； 和(D)定义调节Th1激活的分子和细胞元件， 在有效后贩运和重新招募到生殖器粘膜 沙眼衣原体的细胞和亚单位疫苗接种。来自这些的结果 研究可能会导致开发一种可靠的疫苗方案 对抗衣原体，这应该会对生殖器产生重大影响， 眼部、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.