Role of Immunization Site in Eliciting Mucosal Immunity

免疫位点在引发粘膜免疫中的作用

• 批准号: 6408867
• 负责人: Peter A Anton
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6408867
• 关键词: AIDS vaccines; CD4 molecule; CD8 molecule; HIV infections; active immunization; chemokine; drug administration routes; gut associated lymphoid tissue; human subject; immunoglobulin A; immunoglobulin G; mucosal immunity; patient oriented research

DESCRIPTION (Provided by Applicant): Sexual transmission via a mucosal surface is the most common route for the spread of HIV-1 infection yet little is known about vaccine induction of mucosal immunity to this or any other virus. Methods for evaluating the correlates of protective immunity also remain incompletely defined. It has been previously demonstrated that an immunization protocol using SIV subunits and an optimized adjuvant delivered by targeted iliac lymph node (TILN) injections protected against SIV rectal mucosal challenge while other routes and sites of immunization did not. Protection was correlated with a significant increase of IgA-secreting cells in the lymph nodes, in CD8-suppressor factor and B-chemokine production. Based on these data and awareness of homing patterns, localization of antigen-presenting cells (APCs) and activation state, we suggest that in humans, immunization in regional, draining lymph nodes will provoke more robust mucosal immune responses than systemic (deltoid) immunization and provide enhanced protection from natural HIV infection. As different vaccines may vary in their ability to stimulate both T and B cell mucosal immune responses, we aim to compare mucosal responses in human seronegative volunteers triggered by either TILN or deltoid immunization using two HIV-1 vaccines that are either vaccinia-based (TBC-IIlB) or canarypox-based (ALVAC vCP1452 with gpl40 boost). Mucosal immune responses will be assessed using rectal Iavage and endoscopic biopsies and will include comparisons of specific secretory IgA and IgG, specific CD8 and CD4 responses and B-chemokine production. Systemic immune responses will be tested in parallel. To provide a comparative frame of reference to assess the breadth and potency of vaccine elicited specific anti-HIV-l immune responses, the same mucosal and systemic immune responses will be characterized in HIV-seropositive individuals, including long term nonprogressors, highly exposed persistently seronegatives, chronically infected untreated and chronically infected individuals with suppressed plasma viral loads. This proposal addresses the need to characterize the role of site-specific immunization in eliciting HIV-specific mucosal responses. In addition, the experiments proposed allow a better understanding of HIV-l induced pathogenesis and virus specific responses in this highly vulnerable, sexually exposed, compartment. If the hypothesis is correct and TILN immunization elicits either more diverse or stronger mucosal immunity than peripheral immunization, these findings will impact the way in which HIV-specific vaccines are tested in the future, and may optimize the chances of developing efficacious vaccines, a task that has so far been elusive.

描述（申请人提供）：通过粘膜表面进行性传播 是HIV-1感染传播最常见的途径，但鲜为人知 关于对此或任何其他病毒的粘膜免疫诱导的疫苗。方法 用于评估保护性免疫的相关性也不完全 定义。以前已经证明了免疫协议 使用SIV亚基和针对靶向淋巴的优化佐剂 节点（TILN）注射受到SIV直肠粘膜挑战的保护 免疫的其他路线和部位没有。保护与 淋巴结中的IGA分泌细胞显着增加 CD8-抑制因子和B-脱氧因素的产生。基于这些数据， 对归巢模式的意识，抗原呈递细胞的定位（APC） 和激活状态，我们建议在人类中，区域免疫， 与 系统性（三角肌）免疫，并提供了增强的保护免受自然的保护 艾滋病毒感染。因为不同的疫苗可能在刺激的能力上有所不同 T和B细胞粘膜免疫反应，我们的目的是比较粘膜反应 在人类的血清神经志愿者中，由TILN或DELTOID触发 使用两种基于疫苗的HIV-1疫苗（TBC-IILB）进行免疫接种 或基于CanaryPox的（具有GPL40增压的ALVAC VCP1452）。粘膜免疫反应 将使用直肠iavage和内窥镜活检评估，并将包括 比较特定分泌IgA和IgG，特定CD8和CD4响应的比较 和B-emokine生产。系统性免疫反应将在 平行线。提供比较的参考框架，以评估广度和 疫苗的效力引起了特定的抗HIV-L免疫反应，相同 粘膜和全身免疫反应将以HIV阳性阳性为特征 个人，包括长期非探测器，高度暴露 血浆，长期感染未处理和长期感染的 具有抑制血浆病毒负荷的个体。该提议解决了 需要表征特异性免疫在引起的作用 HIV特异性粘膜反应。此外，提出的实验允许 更好地了解HIV-L诱导的发病机理和病毒特异性反应 在这个高度脆弱，性暴露的隔间中。如果假设是 正确和TILN免疫引起的粘膜更多样化或更强 免疫比外周免疫，这些发现将影响 将来测试了哪种HIV特异性疫苗，并可能优化 开发有效的疫苗的机会，这项任务已经远了 难以捉摸。