TARGETED DNA DELIVERY FOR SALIVARY IGA RESPONSES

针对唾液 IGA 反应的靶向 DNA 递送

• 批准号: 6606149
• 负责人: David W Pascual
• 金额: $ 20.83万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606149
• 关键词: B lymphocyte; Retroviridae; cellular immunity; colony stimulating factor; complementary DNA; cytotoxic T lymphocyte; helper T lymphocyte; humoral immunity; immunization; immunoglobulin A; immunoglobulin G; laboratory mouse; lectin; ligands; mucosal immunity; neutralizing antibody; respiratory epithelium; saliva; tissue /cell culture; transfection /expression vector; vector vaccine; virus protein

DESCRIPTION (Adapted from the Investigator's Abstract): Naked DNA vaccines have shown promise for developing protective immunity by either T helper (Th)1 cell or Th2 cell-dependent responses. However, delivery has been primarily limited to peripheral sites rather than mucosal tissues. Consequently, minimal secretory (s)-IgA responses or immune mucosal Th cells are manifested. To successfully immunize the mucosa, efforts must consider the natural barriers at mucosal surfaces, and effectively target mucosal inductive tissues. In an effort to facilitate optimal mucosal immunity in the oral cavity, studies are proposed to utilize a DNA delivery system whereby the expression plasmid is complexed with a M cell-targeting molecule to ferry the DNA to mucosal inductive tissues following intranasal (i.n.) immunization. Much like live vector vaccine delivery systems which mediate host entry via M cells, it is hypothesized that the M cell ligand, reovirus protein sigma 1, will direct the DNA to the nasal-associated lymphoid tissue (NALT) and shared lymph nodes of the salivary-associated lymphoid tissues (SALT) for the appropriate stimulation of mucosal B and T cell subsets. Thus, the objective for this proposal is to test the effectiveness of this novel vaccine delivery system in promoting salivary s-IgA and IgG antibody responses. To further this effort, studies in Specific Aim 1 are focused in assessing the types and magnitude of mucosal antibody responses and the supportive CD4+ T cells induced following i.n. immunization with the protein sigma 1-directed DNA vaccine. Studies in Specific Aim 2 are focused on optimizing CTL responses by the SALT. For Specific Aim 3, to circumvent the possibility of inducing neutralizing antibodies against protein sigma 1, the M cell lectin from Ulex europaeus, will be tested for its ability to ferry the DNA vaccine to mucosal inductive tissues to elicit antigen-specific salivary antibody responses as well as their supportive CD4+ T cells. The last set of studies to be conducted will assess whether the incorporation of GM-CSF or IL-18 cDNA to co-immunize mice with the vaccine cDNA will improve mucosal IgA responses and mucosal CTL responses. These studies will provide the basis for future development of subunit vaccines to target the NALT for eliciting protective immunity in the oral cavity and SALT.

描述（改编自研究者摘要）：裸DNA疫苗具有 显示有希望通过辅助性T细胞（Th）1 或Th2细胞依赖性应答。然而，交付主要是有限的 而不是粘膜组织。因此，最小 表现出分泌型IgA应答或免疫粘膜Th细胞。到 成功地免疫粘膜，努力必须考虑自然屏障， 粘膜表面，并有效地靶向粘膜诱导组织。中 努力促进口腔中的最佳粘膜免疫，研究 提出利用DNA递送系统，由此表达质粒被 与M细胞靶向分子复合以将DNA运送到粘膜 鼻内（i.n.）次免疫就像生活 介导通过M细胞进入宿主的载体疫苗递送系统， 假设M细胞配体，呼肠孤病毒蛋白sigma 1，将指导 鼻相关淋巴组织（NALT）和共享淋巴结的DNA 唾液相关淋巴组织（SALT）进行适当刺激 粘膜B和T细胞亚群。因此，本提案的目的是 测试这种新型疫苗输送系统在促进 唾液s-IgA和IgG抗体应答。为了进一步推动这一努力， 具体目标1侧重于评估粘膜病变的类型和程度 i.n. 用蛋白质sigma 1定向的DNA疫苗免疫。具体研究 目的2是通过SALT优化CTL应答。对于具体目标3， 以避免诱导针对以下的中和抗体的可能性： 来自欧洲荆豆的M细胞凝集素蛋白sigma 1将被测试其 能够将DNA疫苗运送到粘膜诱导组织， 抗原特异性唾液抗体应答及其支持性CD4 + T细胞 细胞最后一组研究将评估 掺入GM-CSF或IL-18 cDNA以用疫苗cDNA共免疫小鼠 将改善粘膜IgA应答和粘膜CTL应答。这些研究 将为未来开发针对这些疾病的亚单位疫苗提供基础。 NALT用于在口腔和SALT中引发保护性免疫。