Immunity To Chlamydial Infection

对衣原体感染的免疫力

• 批准号: 6506921
• 负责人: HARLAN D CALDWELL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6506921
• 关键词: Chlamydia trachomatis; bacterial antigens; bacterial vaccines; bactericidal immunity; biotechnology; chlamydial disease; disease /disorder model; laboratory mouse; mucosal immunity; vaccine development

The purpose of this work is to define the immunological basis that mediates protective immunity against Chlamydia trachomatis infection of the female genital tract. The long-term goal is to then use this information to develop a safe and efficacious vaccine against chlamydial caused sexually transmitted diseases (STD. The project involves the study of immunity in a murine model of chlamydial infection of the female genital tract. The goal of the work is to identify mechanisms of protective immunity and protective antigens, information that then can used to formulate novel vaccines to test in this pre-clinical model. The long-range goal is to move the most promising of these vaccines to human clinical trials to assess their safety and efficacy in preventing chlamydial STDs. Past studies from this laboratory using gene knock out mice, adoptive transfer of immune T cells, and in vivo depletion of T cell subsets strongly implicate CD4+ Th1 cell mediated immunity as the major protective arm of the immune response against chlamydial genital infection. Conversely, CD8+ T cells, gamma/delta T cells, and antibodies play only a limited role in mediating protective immunity. We have continued studies along these lines to further define effector function(s) of CD4+ Th1 mediated immunity and lymphocyte homing to the genital mucosal. Our findings do not support a role for IFN-gamma, TNF-alpha, iNOS, or Fas mediated apoptopic killing in protective anti-chlamydial mediated T cell immunity. Homing studies implicate both systemic and mucosal integrins and their cognate receptors in lymphocyte homing to the genital mucosa. All attempts to generate protective CD4+ Th1 anti-chlamydial immunity at the genital mucosa using conventional DNA and recombinant antigen vaccine approaches have failed. Infection of the genital tract, or other mucosal sites, is the only highly efficacious way of generating protective immunity against chlamydial genital re-challenge. Because of the difficulty in vaccinating against chlamydial genital infection we have undertaken a novel albeit unconventional approach to chlamydial vaccine development. This approach utilizes adoptive transfer of autologous dendritic cells (DC) pulsed ex vivo with intact non-viable chlamydial organisms. Our results show that in vitro grown DC efficiently phagocytose inactivated chlamydiae. Chlamydial-pulsed DC, but not DC pulsed with inert latex beads, up-regulate the expression of class II, and the T cell co-stimulatory molecules CD40 and CD86. Chlamydial-pulsed DC also up-regulate the expression of T cell differentiating cytokines IL-6, IL-10, IL-12, and TNF-alpha and the chemokines; MIP-3, MIP-1, IP-10, and MCP-1. Chlamydial-pulsed DC were found to be highly efficient in presenting chlamydial antigen(s) to infection sensitized protective CD4+ Th1 cells. Mice adoptively immunized with chlamydial-pulsed DC produced a strong chlamydial specific Th-1 biased immune response. Moreover, immunized mice were found to be as immune to chlamydial genital challenge as post-infection immune animals. Thus, ex vivo antigen pulsed DC represent a very powerful approach for the study of protective immunity to chlamydial infection of the genital mucosa. The use of ex vivo antigen pulsed DC will provide a way to identify chlamydial protective antigens and key immune effector functions that elicit protective immunity at the genital mucosa. Future studies will focus on using DC pulsed ex vivo with DNA based or recombinant protein antigens. These studies should yield information important to the development of more conventional vaccines for the prevention of chlamydial STDs.

这项工作的目的是定义免疫学基础，该免疫基础介导了针对女性生殖道的沙眼衣原体感染的保护性免疫。长期的目标是使用此信息来开发针对衣原体的安全有效的疫苗引起性传播疾病（STD。该项目涉及在女性生殖道的衣原体感染模型中进行免疫研究。该工作的目标是确定抗药性和保护性抗药性的机制，可以识别出这种抗原的方法，以供您进行新型抗药性。远程目标是将这些疫苗的最有希望的人转移到人类临床试验中，以评估其在该实验室的安全性和疗效。 CD8+ T细胞，γ/delta T细胞和抗体在介导保护性免疫中的作用有限。我们沿着这些线路进行了持续研究，以进一步定义CD4+ Th1介导的免疫力和对生殖器粘膜的淋巴细胞的效应函数。我们的发现不支持IFN-GAMMA，TNF-ALPHA，INOS或FAS介导的替代抗室内抗细胞介导的T细胞免疫中介导的凋亡杀伤。归巢研究暗示了全身性和粘膜整合素及其同源受体在淋巴细胞中归因于生殖器粘膜。使用常规DNA和重组抗原疫苗方法在生殖器粘膜下产生保护性CD4+ TH1抗智种免疫的所有尝试都失败了。生殖道或其他粘膜部位的感染是唯一产生对衣原体生殖器再挑战的保护性免疫力的高效方法。 由于难以疫苗接种衣原体生殖器感染，我们采取了一种新颖的方法，尽管对衣原体疫苗发育是非常规的方法。这种方法利用自体树突状细胞（DC）脉冲的过继转移，该脉冲具有完整的无效衣原体生物。我们的结果表明，在体外生长的直流有效地吞噬了被灭活的衣原体。衣原体脉冲的直流，但没有用惰性乳胶珠脉冲的直流，上调了II类的表达，而T细胞共刺激分子CD40和CD86。衣原体脉冲DC还上调了T细胞分化细胞因子IL-6，IL-10，IL-12和TNF-Alpha和TNF-Alpha和趋化因子的表达。 MIP-3，MIP-1，IP-10和MCP-1。发现衣原体脉冲直流在向感染敏感的保护性CD4+ TH1细胞中呈现衣原体抗原方面高效。用衣原体脉冲的DC采用免疫的小鼠产生了强烈的衣原体特异性TH-1偏置免疫反应。此外，发现免疫小鼠与感染后的免疫动物一样，对衣原体生殖器挑战具有免疫性。因此，离体抗原脉冲DC是一种非常有力的方法，用于研究对生殖器粘膜衣原体感染的保护性免疫。使用离体抗原脉冲DC的使用将提供一种方法来鉴定衣原体保护性抗原和关键的免疫效应子功能，从而在生殖器粘膜上引起保护性免疫。未来的研究将集中于使用基于DNA或重组蛋白抗原的DC脉冲离体。这些研究应产生有关开发更多常规疫苗以预防衣原体性病的信息。