Role of Follicular T Helper Cells In Enhancing Humoral Immunity and Protection

滤泡辅助 T 细胞在增强体液免疫和保护中的作用

• 批准号: 8198165
• 负责人: Rafi Ahmed
• 金额: $ 72.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198165
• 关键词: AIDS Vaccines; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affinity; Africa; Animals; Antibodies; Antibody Formation; B-Lymphocytes; BLR1 gene; CD4 Positive T Lymphocytes; Cause of Death; Cell physiology; Cells; Cellular biology; Consensus; DNA/MVA vaccine; Data; Development; Employee Strikes; Encapsulated; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV Antibodies; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunosuppression; In Vitro; Individual; Infection; Instruction; Life; Longevity; Macaca mulatta; Maintenance; Memory B-Lymphocyte; Modeling; Mucosal Immunity; Outcome; Peripheral; Plasma Cells; Process; Proteins; Regimen; Role; SIV; SIV Vaccines; Signal Transduction; Structure of germinal center of lymph node; Surface; Testing; Thailand; Vaccinated; Vaccination; Vaccines; Virus; Virus Replication; acquired immunodeficiency; arm; cytokine; in vivo; mucosal site; nanoparticle; neutralizing antibody; nonhuman primate; prevent; response; vaccine development

Two of the most critical challenges in developing an effecfive AIDS vaccine are to understand how to induce durable immunity at mucosal sites and to define the eariy interactions between HIV and the immune system. In Project 3 we will address both of these issues using the rhesus macaque (RM) model of SIV infection. The precise mechanism by which an AIDS vaccine can confer protective immunity is not known but there is now a general consensus that an effective vaccine should induce both the cellular and humoral arms of the immune system, in particular at the mucosal sites. Recent data from the RV-144 AIDS vaccine trial in Thailand suggest a potential role for antibody in protection from HIV infection. One striking finding from the RV-144 trial was that protection was short-lived and was mostly seen during the first year after vaccination. Thus, a major goal in developing an effective vaccine is to understand how to generate long-lived mucosal immunity. (5D4 T follicular helper (TFH) cells are critical for generating potent and long-lasting anfibody responses and in this project we will determine their role in generating protective humoral immunity following vaccination and infecfion. In our specific aim 1, we will test the hypothesis that long-term humoral immunity is critically dependent on CD4 TFH cells and that the efficient generation of these cells is an essenfial and obligatory component of an effective HIV vaccine. We will examine the magnitude, quality and persistence of SIV specific CD4 TFH cells in both peripheral and mucosal sites after vaccination and determine its correlation to B cell responses. These studies will examine CD4 TFH responses in RMs immunized with DNA/MVA vaccines adjuvanted with GM-CSF (Project 1) and SIV protein immunizafions adjuvanted with TLRs encapsulated in nanoparticles (Project 2). These studies will define which vaccine regimen is most effective in inducing CD4 TFH cells in peripheral and mucosal sites and how the different adjuvants modulate the TFH response and their influence on functional quality and longevity of humoral immunity. In our specific aim 2, we will test the hypothesis that HIV/SIV immunopathogenesis normally precludes the development of a broadly neutralizing anfibody response, but this can be counteracted by immunizafion to generate strong TFH responses before infection. We will determine the suscepfibility of TFH celts to SIV infection and study the infiuence of vaccinafion on their status following infecfion, and the relafionship between the level of virus replicafion in CD4 TFH cells and the main features of SIV infection, including the immune response to the virus and the progression to AIDS.

开发有效的艾滋病疫苗的两个最关键的挑战是了解如何 在粘膜部位诱导持久的免疫力，并确定HIV与免疫系统之间的早期相互作用。 系统在项目3中，我们将使用SIV的恒河猴（RM）模型来解决这两个问题 感染艾滋病疫苗能产生保护性免疫力的确切机制尚不清楚， 现在有一个普遍的共识，即有效的疫苗应该诱导细胞和体液两种武器， 免疫系统，特别是在粘膜部位。RV-144艾滋病疫苗试验的最新数据 泰国建议抗体在防止艾滋病毒感染方面发挥潜在作用。一个惊人的发现， RV-144试验的结果是，保护是短暂的，主要是在接种疫苗后的第一年。 因此，开发有效疫苗的一个主要目标是了解如何产生长寿命的粘膜 免疫力(5D4滤泡辅助性T细胞（TFH）对于产生有效和持久的抗体至关重要。 在本项目中，我们将确定它们在产生保护性体液免疫中的作用， 接种疫苗和感染。 在我们的具体目标1中，我们将检验长期体液免疫是关键的假设。 依赖于CD 4 TFH细胞，这些细胞的有效产生是必要的和强制性的。 一种有效的艾滋病毒疫苗。我们将研究结构性投资工具的规模、质量和持续性 免疫后外周和粘膜部位的特异性CD 4 TFH细胞，并确定其与 B细胞反应。这些研究将检查用DNA/MVA免疫的RM中的CD 4 TFH应答 GM-CSF佐剂疫苗（项目1）和TLR佐剂SIV蛋白免疫 封装在纳米颗粒中（项目2）。这些研究将确定哪种疫苗方案最有效 在外周和粘膜部位诱导CD 4 TFH细胞以及不同佐剂如何调节TFH 反应及其对体液免疫功能质量和寿命的影响。在我们的具体目标2中， 我们将检验HIV/SIV的免疫发病机制通常排除了HIV/SIV的发展这一假设。 广泛中和抗体反应，但这可以通过免疫产生强TFH来抵消 感染前的反应我们将确定TFH细胞对SIV感染的耐受性，并研究TFH细胞对SIV感染的耐受性。 疫苗接种对感染后状态的影响，以及病毒水平 SIV感染的主要特征，包括对CD 4 TFH细胞的免疫应答， 病毒和艾滋病的发展。