In vivo Targeting of Human Dendritic Cell Subsets

人树突状细胞亚群的体内靶向

基本信息

批准号：
7686545
负责人：
GERARD ZURAWSKI
金额：
$ 36.78万
依托单位：
BAYLOR RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7686545
关键词：
Antibiotic Resistance Antibiotics Antibodies Antibody Formation Antigen Presentation Antigens B cell differentiation Binding Biological Biological Warfare Bioterrorism Blood Bone Marrow CD34 gene CD8B1 gene Chimeric Proteins Clinical Communicable Diseases Complement Coupled Cutaneous Defense Mechanisms Dendritic Cells Dengue Development Engineering Evolution Exposure to Generations HIV Hematopoietic stem cells Hepatitis C Human Immune Immune response Immune system Immunity In Vitro Knowledge Langerhans cell Lead Lung Lymphocyte Lymphocyte Function Malaria Measures Memory Mind Modeling Mus Myelogenous Natural Immunity Pre-Clinical Model Process Purpose Respiratory Syncytial Virus Vaccines SCID Mice Series Skin Symptoms T memory cell T-Lymphocyte Testing Tissues Transplantation Tuberculosis Vaccinated Vaccination Vaccine Antigen Vaccines Viral Virus base biothreat chemical conjugate chemotherapeutic agent cytotoxic design desire flu in vivo in vivo Model influenzavirus interstitial lymph nodes novel novel strategies novel vaccines pathogen prevent research study response

项目摘要

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.

项目4：疫苗和抗生素有助于预防或改善许多传染病。但是，很自然用于生物恐怖目的的进化和工程创造了新颖的生物治疗有必要包括i）开发新型化学治疗剂，ii）自然的利用防御机制，即免疫系统。后一个可能包括非特异性激活先天免疫系统和通过疫苗对适应性免疫的操纵。我们现在知道疫苗通过树突状细胞（DC）作用，即免疫效应子的发起人和控制器（T和B 淋巴细胞）分化。正如淋巴细胞由不同的子集组成一样，DC也包括几个差异控制淋巴细胞功能的子集。因此，重要的是要了解DC的不同亚集在体内调节疫苗免疫。这些知识将使我们能够设计有针对性的疫苗将诱导所需的免疫力。该项目旨在i）构建新型的人类疫苗，该疫苗由针对不同的抗体组成人类DC的子集耦合到选择的抗原，无论是化学缀合物还是抗体 - 抗原融合蛋白，以及ii）确定引起的抗原特异性免疫反应的质量和幅度通过靶向人类DC的不同子集，体外和体内。我们将在人类的小鼠中评估免疫系统（Humouse），使用流感的特定细胞和体液免疫反应诱导病毒作为模型病原体。 AIM 1将确定抗DC mAb/流感结合物是否可以诱导流感特异性次级体外反应。 AIM 2将确定抗DC mAb/流感是否靶向不同的DC子集体外的主要免疫反应。 AIM 3将通过选定确定人类DC子集的体内靶向抗DC mAb/流感结合物。 AIM 4将确定特定的抗DC mAb/流感偶联物是否针对体内不同的人类DC子集允许启动流感特异性的保护性免疫反应。这疫苗效力的最终参数将是对Humouse的保护免受病毒的保护。这项研究将导致靶向人类DC亚群的新型疫苗。