Vaccine strategies that target cytolic CD4 T cells to the lung.

将细胞 CD4 T 细胞靶向肺部的疫苗策略。

• 批准号: 7977328
• 负责人: Deborah M. Brown
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977328
• 关键词: Address; Adjuvant; Adjuvanticity; Agonist; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Binding; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Capsid Proteins; Cell Surface Receptors; Cells; Cellular Immunity; Coculture Techniques; Communicable Diseases; Cytokine Signaling; Cytomegalovirus; Data; Dendritic Cells; Dendritic cell activation; Development; Dose; Elderly; Future; Generations; Goals; HIV; Health; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Invaded; Investigation; Knowledge; Lead; Ligands; Lung; Lymphocytic choriomeningitis virus; Mediating; Memory; Morbidity - disease rate; Mus; Peptides; Phenotype; Play; Population; Preparation; Production; Public Health; Receptor Cell; Receptor Signaling; Recovery; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Staging; T cell response; T-Cell Receptor; T-Lymphocyte; TLR4 gene; Testing; Toll-like receptors; Transgenic Organisms; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; Viral; Viral Vaccines; Virus; Virus Diseases; base; cytokine; cytotoxicity; in vitro activity; in vivo; influenza virus vaccine; influenzavirus; mortality; mouse model; neutralizing antibody; next generation; novel vaccines; pandemic disease; pathogen; perforin; peripheral blood; public health relevance; research study; respiratory; response; trafficking; vaccine development

DESCRIPTION (provided by applicant): Respiratory viral infections remain a major health concern causing morbidity and mortality, especially in elderly and immunocompromised individuals. Current vaccines against influenza rely on inducing neutralizing antibodies to coat proteins; however, these vaccines are ineffective against serologically distinct viral strains and strains that have pandemic potential. Therefore, it is of extreme importance to develop influenza vaccines that target T cell immunity, however, the mechanisms that direct T cell trafficking to the lung and the T cell effector mechanisms that correlate with protection have not been fully defined. In addition, it is not known which adjuvants or vaccine preparations are best suited to prime effective T cell responses that persist to memory. To address these gaps in our knowledge, we will use a mouse model of influenza infection and CD4 T cell receptor (TCR) transgenic (tg) mice specific for influenza H1N1 to track the development of CD4 T cell effectors that traffic to the lung, persist to memory and contribute to protection following vaccination. Our previous studies and preliminary data demonstrate that CD4 T cells acquire perforin mediated cytotoxicity following influenza infection and protect against lethal challenge in an antibody independent manner. The objective of this proposal is to determine which vaccine strategies elicit cytolytic CD4 T cells that migrate to the lung and afford protection to lethal influenza infection. We will focus on toll like receptor (TLR) ligands as adjuvants because of their ability to mobilize dendritic cells (DC), potent activators of T cell responses. In Aim 1, we will determine the role of TLR ligands in promoting class II restricted cytolytic activity in vitro and in vivo. The first approach will be to isolate DC populations from the lung, activate with TLR ligands, co-culture with TCR Tg CD4 cells and determine if cytolytic CD4 cells are generated in vitro. The second approach will be to confirm the adjuvant effect of TLR agonists in vivo by transferring naive TCR Tg CD4 cells into mice, vaccinating via the respiratory tract and analyzing the CD4 response in the lung. In Aim 2 we will determine whether vaccine induced cytolytic CD4 cells differentiate to the memory stage and contribute to protection against lethal influenza infection. We will use the TLR ligands that elicit cytolytic CD4 cells as a correlate of protection and test whether those adjuvants induce a memory population and provide protection against a lethal influenza challenge. Finally, using perforin deficient CD4 T cells and B cell deficient mice, we will test whether perforin dependent cytolytic activity is required for antibody independent protection mediated by CD4 T cells. PUBLIC HEALTH RELEVANCE: Respiratory infections such as influenza pose a major public health threat. The proposed studies will further our understanding of how CD4 T cell immunity develops and persists in the lung in response to vaccination with adjuvant preparations that activate the innate immune response. This information will be important for developing novel vaccine strategies that target cell mediated immunity and provide more universal protection against emerging, serologically distinct influenza strains such as H5N1 and H1N1.

描述（由申请方提供）：呼吸道病毒感染仍然是导致发病率和死亡率的主要健康问题，尤其是在老年人和免疫功能低下的个体中。目前针对流感的疫苗依赖于诱导针对外壳蛋白的中和抗体;然而，这些疫苗对血清学上不同的病毒株和具有大流行潜力的病毒株无效。因此，开发靶向T细胞免疫的流感疫苗是极其重要的，然而，指导T细胞运输到肺的机制和与保护相关的T细胞效应器机制尚未完全确定。此外，目前还不知道哪种佐剂或疫苗制剂最适合引发持续记忆的有效T细胞应答。为了解决我们知识中的这些空白，我们将使用流感感染的小鼠模型和对H1N1流感特异性的CD 4 T细胞受体（TCR）转基因（tg）小鼠来跟踪CD 4 T细胞效应物的发展，这些效应物运输到肺部，持续记忆并有助于疫苗接种后的保护。我们以前的研究和初步数据表明，CD 4 T细胞获得穿孔素介导的细胞毒性后，流感感染和保护免受致命的挑战，在抗体的非依赖性方式。本提案的目的是确定哪种疫苗策略引起细胞溶解性CD 4 T细胞迁移到肺部并提供对致命流感感染的保护。我们将重点关注Toll样受体（TLR）配体作为佐剂，因为它们能够动员树突状细胞（DC），T细胞反应的有效激活剂。在目的1中，我们将确定TLR配体在促进II类限制性细胞溶解活性中的作用。第一种方法将是从肺中分离DC群体，用TLR配体活化，与TCR Tg CD 4细胞共培养，并确定是否在体外产生细胞溶解性CD 4细胞。第二种方法将是通过将初始TCR Tg CD 4细胞转移到小鼠中，经由呼吸道接种并分析肺中的CD 4应答来确认TLR激动剂的体内佐剂作用。在目的2中，我们将确定疫苗诱导的溶细胞性CD 4细胞是否分化为记忆阶段并有助于保护免受致命流感感染。我们将使用TLR配体，引发溶细胞性CD 4细胞作为保护的相关性，并测试这些佐剂是否诱导记忆群体，并提供针对致命流感攻击的保护。最后，使用穿孔素缺陷型CD 4 T细胞和B细胞缺陷型小鼠，我们将测试穿孔素依赖性细胞溶解活性是否是由CD 4 T细胞介导的抗体非依赖性保护所必需的。 公共卫生相关性：流感等呼吸道感染对公共卫生构成重大威胁。拟议的研究将进一步了解CD 4 T细胞免疫如何在肺中发展和持续，以响应激活先天免疫应答的佐剂制剂的疫苗接种。这一信息对于开发靶向细胞介导的免疫并提供针对新出现的血清学上不同的流感毒株如H5 N1和H1N1的更普遍的保护的新疫苗策略将是重要的。