PROTECTIVE IMMUNITY IN HUMANS AGAINST O VOLVULUS LARVAE

估计有1800万人感染盘尾丝虫， 将导致100万人视力受损， 超过40万。 虽然药物伊维菌素定期给药 承诺皮肤微丝蚴（MF）密度的急剧降低， 控制程序的严重局限性要求 替代控制战略，如针对 感染期幼虫（L3）和发育中的第四期幼虫 （LA）. 先前的研究提供了证据， 对O.人类可能发生扭转感染。 这 该项目是一项雄心勃勃的尝试， 暴露于感染但不具有免疫力的脓毒症免疫（PI）个体 而不是被感染。 对O.肠扭转感染 PI已显示与TH 1型细胞 当针对OvAg、蠕虫提取物进行测试时， 然而，在这方面， 发现抗L3 TH2型应答与保护作用相关 在手术肠扭转小鼠扩散室模型。 此外还有 有证据表明耐药性也可能是由抗体介导的， PI血清可以识别独特的幼虫阶段特异性蛋白。 我们假设，人类的保护性免疫可以通过以下方式引起： 幼虫抗原，它的运作独立于免疫反应 成人抗原或MF。 为了验证这个假设，我们将：1。分析 对粗抗原的细胞和体液免疫反应 PI与受感染的个体相比，从而提供 缺乏与保护性免疫反应相关的信息 免疫力，并专门针对感染性 寄生虫的阶段 2.鉴定和克隆幼虫蛋白， 被PI的抗L3保护性免疫应答靶向，然后 分析PI中对相应重组体的免疫应答 蛋白质，以确定候选分子用于 免疫和诱导保护的小鼠扩散室 针对O. L3肠扭转激发。 重点是抗原 在L3到L4的蜕皮期间表达，正如许多以前的结果一样， 指出这些抗原是潜在的保护诱导物， 效应器机制的目标。3.测试疫苗的效力 选择克隆的重组抗原。 其中一个主要目标是 一个项目是发现重组蛋白， 免疫小鼠扩散室模型，从而推进 开发一种供人类使用的疫苗。 这些研究应该， 因此，有助于开发疫苗， 具有预期临床应用的盘尾丝虫病。

An estimated 18 millions are infected with Onchocerca volvulus which will result in visual impairment in one million and blindness in more than 400,000. Although periodic administration of the drug ivermectin promise a drastic reduction in the densities of skin microfilariae (mf), the severe limitations of the control programs demand the availability of alternative strategies for control, such as vaccines that target the infective stage larvae (L3) and the developing fourth-stage larvae (LA). Previous studies have provided evidence that naturally acquired immunity against O. volvulus infection can occur in humans. This project represents an ambitious attempt to study immunity in the putatively immune (PI) individuals who are exposed to infection but do not become infected. Natural immunity against O. volvulus infection in the PI has been shown to be associated with TH1-type of cellular responses when tested against OvAg, adult worms extracts. However, anti-L3 TH2-type responses were found to be associated with protection in the O. volvulus mouse-diffusion chamber model. In addition, there is some evidence that resistance may be also mediated by antibodies, and that the PI sera can identify unique larval stage-specific proteins. We hypothesize that protective immunity in humans can be elicited by larval antigens, and that it operates independently of immune responses to adult antigens or mf. To test this hypothesis we will: 1. Analyze the cellular and humoral immune responses to crude larval antigens in the PI in comparison to the infected individuals, and thus provide the missing information on immune responses associated with protective immunity and which are directed specifically against the infective stages of the parasite. 2. Identify and clone larval proteins that are targeted by anti-L3 protective immune responses of the PI, and then analyze the immune responses in the PI to the corresponding recombinant proteins in order to determine the candidate molecules to be used in the mouse-diffusion chamber for immunization and the induction of protection against O. volvulus L3 challenge. The emphasis will be on antigens expressed during molting from L3 to L4, as many of the previous results point to those antigens as potential inducer of protection and the target of effector mechanisms. 3. Test the vaccine efficacy of the selected cloned recombinant antigens. One of the major goals of this project is to discover recombinant proteins which can elicit protective immunity in the mouse-diffusion chamber model, and thus advance the development of a vaccine for human use. These studies should, therefore, be instrumental in developing a vaccine against onchocerciasis with anticipated clinical application.