In vivo Targeting of Human Dendritic Cell Subsets

项目4：疫苗和抗生素有助于预防或减轻许多传染病。然而，自然 生物恐怖主义的进化和工程创造了新的生物威胁， 包括i）开发新的化学治疗剂，和ii）利用天然的 防御机制，即，免疫系统.后一种可能包括非特异性激活 先天免疫系统和通过疫苗操纵适应性免疫。我们现在知道 疫苗通过树突状细胞（DC）起作用，树突状细胞是免疫效应物（T和B）的启动者和控制者 淋巴细胞）分化。正如淋巴细胞由不同的亚群组成，DC包括几个亚群。 亚群差异控制淋巴细胞功能。因此，重要的是要了解不同的DC 亚群在体内调节疫苗免疫。这些知识将使我们能够设计出靶向疫苗， 会产生一种免疫力 该项目旨在i）构建由针对不同的抗体组成的新型人类疫苗， 与所选抗原偶联的人DC亚群，作为化学缀合物或作为抗体-抗原 融合蛋白，和ii）确定在细胞中引发的抗原特异性免疫应答的质量和幅度， 通过靶向人DC的不同亚群在体外和体内进行。我们将评估，在小鼠与人类 免疫系统（Humouse），使用流感病毒诱导特异性细胞和体液免疫应答 病毒作为模式病原体。 AIM 1将确定抗DC mAb/Flu偶联物是否能诱导Flu特异性第二免疫应答。 体外反应。AIM 2将确定靶向不同DC亚群的抗DC mAb/Flu偶联物是否 体外引发免疫反应。AIM 3将通过选择的靶向方法确定人DC亚群的体内靶向。 抗DC mAb/Flu偶联物。AIM 4将确定特异性抗DC mAb/Flu偶联物是否靶向 体内不同的人DC亚群允许引发流感特异性保护性免疫应答。的 疫苗效力的最终参数将是Humouse对病毒再攻击的保护。 这项研究将导致产生新的疫苗靶向的人DC亚群在体内。

Project 4: Vaccines and antibiotics help prevent or ameliorate many infectious diseases. Yet, natural evolution and engineering for bioterrorism purposes create novel biothreats for which novel countermeasures are necessary including i) development of novel chemotherapeutic agents, and ii) utilization of natural defense mechanisms, i.e., the immune system. The latter one may include non-specific activation of the innate immune system and manipulation of the adaptive immunity through vaccines. We now know that vaccines act through dendritic cells (DCs), the initiators and controllers of immune effectors (T and B lymphocytes) differentiation. Just as lymphocytes are composed of different subsets, DCs comprise several subsets that differentially control lymphocyte function. It is therefore important to understand how distinct DC subsets modulate vaccine immunity in vivo. Such knowledge will permit us to design targeted vaccines that will induce a desired type of immunity. This project is designed to i) construct novel human vaccines comprised of antibodies targeting distinct subsets of human DCs coupled to an antigen of choice, either as chemical conjugates or as antibody-antigen fusion proteins, and ii) determine the quality and magnitude of antigen-specific immune responses elicited in vitro and in vivo by targeting distinct subsets of human DCs. We will evaluate, in the mice with a human immune system (Humouse), the induction of specific cellular and humoral immune responses using Influenza virus as a model pathogen. AIM 1 will determine whether anti-DC mAb/Flu conjugates can induce Flu-specific secondary responses in vitro. AIM 2 will determine whether anti-DC mAb/Flu conjugates that target different DC subsets prime immune responses in vitro. AIM 3 will determine the in vivo targeting of human DC subsets by selected anti-DC mAb/Flu conjugates. AIM 4 will determine whether specific anti-DC mAb/Flu conjugates targeted to distinct human DC subsets in vivo permit the priming of Flu-specific protective immune responses. The ultimate parameter of vaccine potency will be the protection of Humouse from virus rechallenge. This study will lead to generation of novel vaccines targeted to human DC subsets in vivo.