DC-subset-tailored vaccines

DC亚群定制疫苗

• 批准号: 10404526
• 负责人: Botond Z Igyarto
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-17 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404526
• 关键词: Acquired Immunodeficiency Syndrome; Adoptive Cell Transfers; Adoptive Transfer; Allergic Disease; Antibodies; Antibody Affinity; Antibody Response; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Antiviral Response; Autoimmune Diseases; B-Lymphocytes; BLR1 gene; Bone Marrow; Breeding; Cell Culture Techniques; Cells; Chimera organism; Coculture Techniques; Communicable Diseases; Data; Dendritic Cells; Dependence; Development; Disease; Dose; Elements; Experimental Models; Flow Cytometry; Generations; Goals; HIV; Helper-Inducer T-Lymphocyte; Humoral Immunities; Image; Immune response; Immunize; In Vitro; Influenza; Influenza Hemagglutinin; Interleukin-6; Knock-out; Knowledge; Langerhans cell; LoxP-flanked allele; Mission; Molecular; Mus; Outcome; Peptide/MHC Complex; Phenotype; Physiologic pulse; Play; Population; Prevention; Prevention approach; Process; Public Health; Regulation; Research; Role; Site; Skin; Structure of germinal center of lymph node; System; Testing; Time; Transgenic Mice; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Work; adaptive immune response; base; design; experimental study; feasibility testing; human disease; imprint; in vivo; influenza virus vaccine; innovation; langerin; mouse model; novel; prevent; rational design; receptor; response; universal influenza vaccine; universal vaccine

PROJECT SUMMARY There is a fundamental gap in our understanding of why only certain vaccines promote formation of long-lasting and protective antibody responses. Dendritic cells (DC) are professional antigen presenting cells that regulate adaptive immune responses; thus, we think that understanding the role DCs in regulating B cell responses will be key to the development of universal vaccines targeting influenza and HIV. Our experimental data suggest that the major limitations of the relatively ineffective vaccines currently in use or in development might be that: 1) they do not specifically target Langerhans cells (LCs) and 2) the antigen dose is not tailored to maximize the activation of the LCs. Our long-term goal is to understand the role of different DC populations in humoral immune responses and to use that knowledge to design DC-subset-tailored vaccines, with a special focus on influenza and HIV. In pursuit of that goal, the objectives of this application are to: 1) define the mechanisms by which steady state LCs promote germinal center (GC)-dependent humoral immune responses; 2) to characterize the regulatory loop by which high antigen dose and CD103+ DCs inhibit GC-dependent responses induced by LCs; and 3) to test the feasibility of the DC-subset-tailored influenza vaccine. Our central hypothesis is that LCs drive functionally distinct Tfh cells in an antigen dose-dependent manner that ultimately determines whether humoral immune responses are mounted or not. The rationale for the proposed research is that, once the details of how LCs initiate humoral immune responses and regulate each other are known, the process can likely be manipulated to yield innovative approaches for prevention and treatment of a variety of diseases. Guided by strong preliminary data, our hypothesis will be tested in these three Specific Aims: 1. Define the mechanism by which LCs promote GC-dependent humoral immune responses; 2) Determine the mechanism by which high antigen dose and CD103+ DCs inhibit LC-induced GC-dependent humoral immune responses; and 3) Determine the effect of antigen dose on development of protective anti-viral responses. For Aim 1, a well characterized targeting approach will be combined with LC-specific knock out transgenic mouse models, bone marrow chimeras, imaging, in vitro cell cultures and flow cytometry to define the molecular requirements of LC-induced humoral immune responses. In Aim 2, in vitro co-culture experiments and in vivo adoptive cell transfer systems will be used to characterize how high antigen dose and CD103+ DCs regulate LC-induced immune responses. In Aim 3, we will immunize mice through LCs with different doses of flu-HA and then challenge with live influenza to determine the feasibility of the antigen-tailored influenza vaccine. The proposed hypothesis and experimental models are highly novel and innovative. This project is significant because it will advance and expand our understanding on how humoral immune responses are induced and regulated by DC subsets, which we expect will overcome problems that have hindered our ability to generate effective influenza vaccines.

项目摘要 我们对为什么只有某些疫苗促进持久形成的理解存在根本的差距 和保护性抗体反应。树突状细胞（DC）是调节的专业抗原呈现细胞 自适应免疫反应；因此，我们认为了解DC在调节B细胞反应中的作用将 是靶向流感和艾滋病毒的通用疫苗开发的关键。我们的实验数据表明 目前正在使用或开发的相对无效的疫苗的主要局限性可能是： 1）它们不具体靶向兰格汉细胞（LCS）和2）抗原剂量并非量身定制以最大化 LCS的激活。我们的长期目标是了解不同DC种群在体液免疫中的作用 回答并利用这些知识来设计DC-Subset-Tail-Tail-Tail-Tail疫苗，特别关注流感 和艾滋病毒。为了追求该目标，本应用的目标是：1）定义的机制 稳态LCS促进生发中心（GC）依赖性体液免疫反应； 2）表征 高抗原剂量和CD103+ DC抑制LCS诱导的GC依赖性反应的调节环； 3）测试DC-Subset-tail-tail-tail tailza流感疫苗的可行性。我们的中心假设是LCS驱动 功能上不同的TFH细胞以抗原剂量依赖性方式最终决定是否体液 免疫反应是否安装。拟议的研究的理由是，一旦有关如何 LCS启动体液免疫反应并相互调节是已知的，该过程可能是 被操纵以产生创新方法，以预防和治疗各种疾病。指导 强大的初步数据，我们的假设将在这三个具体目的中进行检验：1。通过 LCS促进了GC依赖性的体液免疫反应； 2）确定高高的机制 抗原剂量和CD103+ DC抑制LC诱导的GC依赖性体液免疫反应； 3）确定 抗原剂量对保护性抗病毒反应的发展。对于AIM 1，一个有很好的特征 靶向方法将与LC特异性敲除转基因小鼠模型（骨髓）结合 嵌合体，成像，体外细胞培养和流式细胞术，以定义LC诱导的分子需求 体液免疫反应。在AIM 2中，体外共培养实验和体内收养细胞转移系统 将用于表征高抗原剂量和CD103+ DC如何调节LC诱导的免疫反应。 在AIM 3中，我们将通过不同剂量的流感HA的LC免疫小鼠，然后用活流感来挑战 确定抗原量的流感疫苗的可行性。提出的假设和实验 模型是高度新颖和创新的。该项目很重要，因为它将推进和扩展我们 了解如何通过直流子集诱导和调节体液的体液免疫反应，我们期望这 将克服阻碍我们产生有效流感疫苗的能力的问题。