Dendritic Cell Targeting of Anthrax Vaccine

描述(申请人提供)：炭疽病作为生物战的一种媒介，构成了巨大的威胁。目前的炭疽疫苗(AVA)需要在18个月内多次接种。因此，除了目前的疫苗外，改进的炭疽疫苗策略将为公众健康提供帮助。保护性抗原(PA)抗体在炭疽特异性免疫中起重要作用。然而，细胞介导的免疫反应也很重要。专业抗原提呈树突状细胞(DC)具有诱导体液和细胞免疫应答的能力。这些细胞准备捕获病原体，迁移到引流淋巴结，并选择抗原特异性T细胞来调节T、B和NK细胞、巨噬细胞和嗜酸性粒细胞，所有这些都可能有助于保护性免疫。这项建议的目的是开发一种新的针对炭疽PA的疫苗策略，直接针对DC。最近，我们发现树突状细胞在体内和体外都能诱导显著的T细胞活化。此外，我们的初步数据表明，重组PA可以激活DC，诱导共刺激分子的上调，并在体内诱导LC迁移。我们已经从噬菌体展示文库中产生了与DC亚群特异结合的多肽。我们假设，将PA直接靶向DC将增加特定免疫反应的水平和持续时间，从而更好地预防炭疽病。因此，我们将通过将PA与DC特异性多肽融合来靶向DC。本研究的具体目的是：1.确定针对DC的PA是否能增强针对炭疽杆菌PA的特异性免疫应答；2.检测皮下注射PA-DC多肽融合蛋白是否能在免疫活性细胞中诱导强烈的免疫应答。这一新的疫苗策略通过DC结合肽将免疫原性PA靶向DC，可以增强PA的免疫原性，从而诱导更强的针对炭疽杆菌PA的免疫应答。

DESCRIPTION (provided by applicant): Anthrax poses a significant threat as an agent of biological warfare. The current anthrax vaccine (AVA) requires multiple doses over an 18 month period. Therefore, in addition to the current vaccine, improved anthrax vaccine strategies will offer the public health. Antibodies to the protective antigen (PA) play an important role in specific immunity to anthrax. However, cell mediated immune responses are also important. Professional antigen presenting dendritic cells (DCs) possess the ability to elicit both humoral and cellular immune responses. These cells are poised to capture pathogens, migrate to draining lymph nodes, and select antigen-specific T cells to regulate T, B, and NK cells, macrophages and eosinophils, all of which may contribute to protective immunity. The objective of this proposal is to develop a novel vaccine strategy targeting anthrax PA directly to DCs. Recently we have shown that DCs induce significant T cell activation in vivo and in vitro. Moreover, our preliminary data demonstrate that recombinant PA activates DCs, inducing up-regulation of co-stimulatory molecules, and LC migration in vivo. We have generated peptides that specifically bind to DC subsets from a phage display library. We hypothesize that targeting PA directly to DCs will increase the levels and duration of a specific immune response resulting in better protection against anthrax. Thus, we will target PA to DCs by fusing it to DC-specific peptides. The specific aims of this proposal are 1: To determine whether targeting PA specifically to DCs enhances specific immune responses against B. anthracis PA and 2: To test whether PA-DC peptide fusion protein delivered by subcutaneous administration induces strong immune responses in the immune competent cells. This novel vaccine strategy to target specifically immunogenic PA to DCs via DC-binding peptides may enhance the immunogenicity of PA and thus elicit stronger immune responses against PA of B. anthracis.