ANTICHLAMYDIAL PROTECTION BY MOLECULAR MIMCRY

分子模拟的抗衣原体保护

基本信息

批准号：
6170762
负责人：
JUDITH A. WHITTUM-HUDSON
金额：
$ 25.28万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-06-01 至 2003-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the applicant's abstract): Chlamydia trachomatis is the leading cause worldwide of sexually transmitted disease and the most prevalent ocular pathogen. In addition to being the major cause of non-gonococcal urethritis and pelvic inflammatory disease, chlamydia are also the leading cause of preventable infectious blindness (trachoma) and are also associated with arthritis in a significant number of patients with Reiter's syndrome/Reactive arthritis. The public health costs of chlamydial infections and their sequelae are enormous. Identification of a protective anti-chlamydial vaccine would have important public health significance. We propose studies in a BALB/c ocular infection model induced by a human chlamydial biovar to further characterize the demonstrated long-lasting protective immunity against ocular infection induced by oral or systemic immunization with a monoclonal anti-idiotypic antibody (mAb2). The mAb2 is a functional and molecular mimic of the genus-specific chlamydial glycolipid exo-antigen, GLXA. We hypothesize that the basis for anti-id induced protection is that detrimental Th1- driven responses are shifted to Th2-mediated protection and that the targeted specificity for GLXA rather than for surface proteins such as MOMP accounts for the protective responses. Since the anti-id is an immunogenic protein, it induces more effective immune responses than would be induced by the glycolipid GLXA Ag itself. Studies will be performed to test this hypothesis using primarily the mouse ocular model as a mucosal infection paradigm; immunization with the mAb, vaccine candidate will be used to (1) characterize the relative role of T and B cells in protective responses, (2) distinguish between requirements for mucosal versus systemic immunization with encapsulated vaccine, (3) determine requirements for maximal protection including adjuvants or additional chlamydial antigens in a cocktail vaccine, and (4) test for anti-id- induced protection in other chlamydial infection models including C. trachomatis and C. psittaci genital infection and arthritides. Humoral responses in sera and secretions and cytokine responses will be used to define the Th1 and Th2 components of protective immunity; immunohistochemistry, in situ hybridization, RT-PCR methods and functional assays will be used in normal and immunodeficient mice to distinguish local and systemic immune responses which correlated with reduced microbiologic and clinical disease. These studies will potentially reveal strategies to assess protection against chlamydial disease induced by other vaccine candidates.

描述（改编自申请人的摘要）：沙眼衣原体是全世界性传播疾病的主要原因最常见的眼部病原体。除了成为主要原因之外非淋菌性尿道炎和盆腔炎、衣原体感染也是可预防的传染性失明（沙眼）的主要原因也与大量患者的关节炎有关患有赖特综合征/反应性关节炎。公共卫生费用衣原体感染及其后遗症是巨大的。鉴定保护性抗衣原体疫苗对公共卫生具有重要意义意义。我们建议在 BALB/c 眼部感染模型中进行研究由人类衣原体生物变种诱导，以进一步表征表现出针对眼部感染的持久保护性免疫力通过口服或全身免疫单克隆抗独特型疫苗诱导抗体（mAb2）。 mAb2 是功能和分子模拟物属特异性衣原体糖脂外切抗原，GLXA。我们假设抗 ID 诱导保护的基础是有害的 Th1- 驱动反应转向 Th2 介导的保护，并且针对 GLXA 而不是针对表面蛋白（例如 MOMP 解释了保护性反应。由于抗 ID 是免疫原性蛋白质，它比普通蛋白质更能诱导有效的免疫反应由糖脂 GLXA Ag 本身诱导。研究将进行主要使用小鼠眼模型作为粘膜来检验这一假设感染范式；使用单克隆抗体进行免疫接种，候选疫苗将是用于 (1) 表征 T 细胞和 B 细胞在保护性中的相对作用反应，（2）区分粘膜和粘膜的要求用胶囊化疫苗进行全身免疫，（3）确定最大保护的要求，包括佐剂或额外的鸡尾酒疫苗中的衣原体抗原，以及 (4) 抗 id- 测试在其他衣原体感染模型中诱导保护，包括 C. 沙眼衣原体和鹦鹉热衣原体生殖器感染和关节炎。幽默的血清和分泌物中的反应以及细胞因子反应将用于定义保护性免疫的 Th1 和 Th2 组成部分；免疫组织化学、原位杂交、RT-PCR 方法和功能检测将用于正常小鼠和免疫缺陷小鼠以区分局部和全身免疫反应与减少相关微生物学和临床疾病。这些研究可能会揭示评估对衣原体疾病的保护作用的策略其他候选疫苗。