Targeting Dendritic Cells for Enhanced Musocal Immunity

靶向树突状细胞以增强肌肉免疫

• 批准号: 7696435
• 负责人: Jacques F Banchereau
• 金额: $ 39.27万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696435
• 关键词: Affinity; Antibodies; Antibody Formation; Antigens; Avidity; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Chimeric Proteins; Communicable Diseases; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Fc Receptor; Generations; Goals; Helper-Inducer T-Lymphocyte; Homing; Human; Immune response; Immunity; Immunoglobulin A; In Vitro; Influenza; Lectin; Major Histocompatibility Complex; Monoclonal Antibodies; Mucosal Immunity; Mucous Membrane; Nucleoproteins; Peptides; Plasma Cells; Proteins; Public Health; Quality Control; Site; Specificity; Surface; T-Lymphocyte; Vaccination; Vaccines; Viral; antigen processing; base; burden of illness; improved; in vivo; influenzavirus; novel; pathogen; receptor; response; vaccine development

Dendritic Cells (DCs) are specialized to capture and process antigens in vivo, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules and recognized by T cells. Maturation and subsets allow DCs to control the diverse immune responses. To harness DCs for vaccination, we have made high affinity monoclonal antibodies against more than ten DC surface molecules. We have shown DCs control the quality of immune responses by taking up antigens through different DC-lectins. Our overall long-term goal is the development of novel human vaccines based on in vivo DC-targeting. The current focus is on mucosal immunity because mucosa is a major site of invasion as well as replication of pathogens, including influenza virus. Thus, priming of two major effectors, B cells and CD8+ T cells, with mucosal homing capacity is expected to limit viral replication, resulting in reduced disease burden. Furthermore, induction of CD4+ T cells with helper functions for B cells or CTLs will enhance the magnitude and the quality of mucosal homing effectors. The current objective to determine novel DC-targeting vaccines that prime mucosal homing antibody-secreting plasma cells and polyfunctional high avidity CD8+ T cells with broad specificity with the help from appropriate type of CD4+ T cells. Hypothesis: Antigen-specific mucosal immunity can be efficiently induced by a DC-targeting vaccine composed of a unique combination of a specific anti-DC receptor antibody, antigen, and DC activator. AIM 1: To identify a combination of anti-DC fusion protein and DC activator that allows DCs to induce potent antigen-specific mucosal antibody responses in vitro. AIM 2: To identify a combination of anti-DC fusion protein and DC activator that allow DCs to induce polyfunctional and mucosal-homing CD8+ T cells in vitro. AIM 3: To identify combinations of anti-DC fusion protein and DC activator that induce helper CD4+ T cells for potent mucosal humoral responses and CTL responses. Thus, we will establish an optimal combination(s) of anti-DC fusion proteins and DC activators which potently induce mucosal antibody and/or CTL responses.

树突状细胞（DC）专门用于在体内捕获和加工抗原，将蛋白质转化为抗原。 主要组织相容性复合体（MHC）分子上呈递并被T 细胞成熟和亚群允许DC控制多种免疫应答。利用DC， 免疫接种后，我们已经制备了针对十多个DC表面的高亲和力单克隆抗体， 分子。我们已经证明，DC通过以下途径摄取抗原来控制免疫应答的质量： 不同的DC-凝集素。我们的总体长期目标是开发新型人类疫苗， 体内DC靶向。目前的重点是粘膜免疫，因为粘膜是主要的侵袭部位， 以及病原体包括流感病毒的复制。因此，两种主要效应物B细胞和 具有粘膜归巢能力的CD 8 + T细胞预期会限制病毒复制，从而减少 疾病负担。此外，诱导具有B细胞或CTL辅助功能的CD 4 + T细胞将 增强粘膜归巢效应物的数量和质量。 目前的目的是确定新的DC靶向疫苗，引发粘膜归巢 分泌抗体的浆细胞和多功能高亲合力CD 8 + T细胞，具有广泛的特异性， 适当类型的CD 4 + T细胞的帮助。假设：抗原特异性粘膜免疫可以 由DC靶向疫苗有效诱导，所述DC靶向疫苗由特异性抗DC 受体抗体、抗原和DC激活剂。目的1：鉴定抗DC融合蛋白与 DC激活剂，允许DC在体外诱导有效的抗原特异性粘膜抗体应答。目标2： 鉴定抗DC融合蛋白和DC激活剂的组合，其允许DC诱导多功能的 和体外粘膜归巢的CD 8 + T细胞。目的3：鉴定抗DC融合蛋白与DC的结合 活化剂，其诱导辅助性CD 4 + T细胞用于有效的粘膜体液应答和CTL应答。因此，在本发明中， 我们将建立抗DC融合蛋白和DC激活剂的最佳组合， 诱导粘膜抗体和/或CTL应答。