Harnessing Human DC Subsets for Improved Muscosal Vaccines

疫苗接种代表了医学的主要成功之一，因为它使无数人免于 小儿麻痹症、破伤风和其他急性传染病。然而，需要改进免疫战略， 针对致病微生物的疫苗。为了确定新的保护策略， 疫苗接种我们将研究树突状细胞（DCs），其专门在体内捕获和加工抗原， 将MHC分子呈递给T细胞。DC还向B细胞呈递抗原。成熟度和子集 允许DC控制多种免疫应答。我们的长期目标是开发新型人类疫苗 基于体内DC靶向。我们的假设是人树突状细胞亚群表达不同的摄取， 和信号受体，它们需要协同调动，以提供持久的免疫反应， 对进入粘膜口的微生物的抵抗力增强。为此，我们做出了高亲和力 针对几种DC表面分子的单克隆抗体，并将它们与几种流感病毒缀合， 病毒蛋白我们已经证明，通过不同的途径将抗原递送到单一类型的人DC， 表面凝集素诱导不同类型抗原特异性CD 4 + T细胞应答。目前的重点是 粘膜免疫，因为粘膜是病原体入侵和复制的主要部位，包括 流感病毒。因此，两种主要效应物B细胞和CD 8 + T细胞的诱导/活化与粘膜免疫应答有关。 归巢能力预计将限制病毒复制，从而减少疾病负担。此外，委员会认为， 诱导具有B细胞或CTL辅助功能的CD 4 + T细胞将增强记忆的寿命 细胞以及粘膜归巢效应物的数量和质量。我们将候选疫苗视为 双特异性抗体a）结合两种不同的细胞表面抗原，如抗原特异性凝集素 递送和CD 40用于活化，或两种不同的DC亚群，以利用它们诱导不同的 类型的免疫效应物，以及另外B）TLR激动剂作为DC激活剂。我们提出了四个项目， 两个技术开发部分，将由六个核心提供支持。

Vaccination represents one of the major successes of medicine as it has spared countless people from polio, tetanus and other acute infections. Yet, improved immunization strategies are needed to make vaccines for microbes that cause considerable morbidity . To identify novel strategies for protective vaccination we will study dendritic cells (DCs) which specialized to capture and process antigens in vivo, presenting the MHC molecules to T cells. DCs also present antigens to B cells. Maturation and subsets allow DCs to control diverse immune responses. Our long-term goal is to develop novel human vaccines based on in vivo DC-targeting. Our hypothesis is that Human Dendritic cells subsets express distinct uptake and signaling receptors that need to be mobilized in concert to provide durable immune responses leading to increased resistance to microbes at the mucosal port of entry. To this end, we have made high affinity monoclonal antibodies against several DC surface molecules and conjugated them to several influenza virus proteins. We have shown that antigens delivered to a single type of human DCs through different surface lectins induce distinct types of antigen-specific CD4+ T cell responses. The current focus is on mucosal immunity because mucosa is a major site of invasion as well as replication of pathogens, including influenza virus. Thus, the induction/activation of two major effectors, B cells and CD8+ T cells, with mucosal homing capacity is expected to limit viral replication, resulting in reduced disease burden. Furthermore, induction of CD4+ T cells with helper functions for B cells or CTLs will enhance the longevity of memory cells and the magnitude and the quality of mucosal homing effectors. We view the candidate vaccine as a bispecific antibody a) binding to two different cell surface antigens, such as specific lectin for antigen delivery and CD40 for activation, or to two different DC subsets, to harness their capacity to induce different type of immune effectors, and in addition b)TLR agonists as DC activators. We propose four projects and two technical development components which will be supported by six cores.