Manipulation of immunodominance to promote heterosubtypic immunity to Influenza

操纵免疫优势促进流感异亚型免疫

• 批准号: 7222721
• 负责人: Andrea Janine Sant
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222721
• 关键词: Avian Influenza; CD4 Positive T Lymphocytes; Cells; DR1 gene; Epitopes; Goals; HLA-DR Antigens; Hemagglutinin; Human; Immunity; Influenza; Influenza A Virus, H5N1 Subtype; Influenza Hemagglutinin; Kinetics; Laboratories; Peptides; Proteins; T-Lymphocyte Epitopes; Transgenic Mice; Vaccine Design; Vaccines; Variant; Virus; Virus Diseases; design; influenzavirus; novel; pandemic disease; pathogen; research study; response

DESCRIPTION (provided by applicant): The major goal of the experiments outlined in this R21 proposal is to promote heterosubtypic immunity to influenza virus infection. Influenza is a significant human pathogen for which there is no available vaccine1 that promotes persistent and effective immunity. This is a particularly urgent objective of late because of the emergence of a highly pathogenic H5N1 strain of avian influenza that has passed to humans, creating a potential threat of a pandemic. Recently, our laboratory has developed a novel and successful strategy to manipulate immunodominance in CD4 T cell responses. In this proposal, we wish to use this strategy to explore whether intentional focus of the CD4 T cell response toward epitopes shared among subtypes of influenza, particularly those expressed within the H5 subtype, will promote protective heterosubtypic immunity. Because of the direct implication of these studies on human vaccine design, we will perform these experiments using peptides presented by human HLA-DR molecules and DR1-transgenic mice. We will derive novel HA peptide-containing protein constructs to drive intentional focus of the CD4 T cell response towards hemagglutinin epitopes that are highly conserved among serologically distinct HA subtypes. Specific Aim 1: Identification of immunodominant DR1-restricted CD4 T cell epitopes to influenza HA. Specific Aim 2: Design and utilize kinetic stability variants of HA-derived peptides to promote immunodominance. Specific Aim 3. Promoting focus of the CD4 T cell responses toward conserved epitopes and protection to virus challenge.

描述（由申请人提供）：本 R21 提案中概述的实验的主要目标是促进对流感病毒感染的异亚型免疫。流感是一种重要的人类病原体，目前尚无可用的疫苗1来促进持久和有效的免疫力。这是最近一个特别紧迫的目标，因为高致病性 H5N1 禽流感病毒株的出现已经传染给人类，造成了大流行的潜在威胁。最近，我们的实验室开发了一种新颖且成功的策略来操纵 CD4 T 细胞反应中的免疫优势。在本提案中，我们希望利用这一策略来探讨 CD4 T 细胞对流感亚型（特别是 H5 亚型内表达的表位）共享表位的有意关注是否会促进保护性异亚型免疫。由于这些研究对人类疫苗设计的直接影响，我们将使用人类 HLA-DR 分子和 DR1 转基因小鼠呈现的肽进行这些实验。我们将衍生出新的含 HA 肽的蛋白质构建体，以驱动 CD4 T 细胞对血凝素表位作出有意的反应，这些表位在血清学上不同的 HA 亚型中高度保守。具体目标 1：鉴定流感 HA 的免疫显性 DR1 限制性 CD4 T 细胞表位。具体目标 2：设计并利用 HA 衍生肽的动力学稳定性变体来促进免疫优势。具体目标 3. 促进 CD4 T 细胞对保守表位的反应和对病毒攻击的保护。