EPITOPE DELIVERY, IMMUNODOMINANCE AND VACCINE EFFICACY

表位递送、免疫优势和疫苗功效

• 批准号: 2898534
• 负责人: H. G. Archie Bouwer
• 金额: $ 18.39万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2898534
• 关键词: Listeria; bacterial antigens; bactericidal immunity; cellular immunity; cytotoxic T lymphocyte; immunoregulation; laboratory mouse; vaccine development; vector vaccine

DESCRIPTION (adapted from applicant's abstract): The protective immune response to L. monocytogenes is used to investigate general features of cell-mediated immunity to intracellular bacteria. In BALB/c mice, Listeria-specific CD8+ CTL have been isolated which are Kd restricted. Peptides from listeriolysin O (LLO) a molecule secreted in the phagocytic vacuole, and p60, a molecule that is abundantly secreted in the cytoplasm, have been identified as CTL targets. CTL frequency analysis shows that the LLO-derived determinant, LLO 91-99, is immunodominant. We hypothesize that secretion of LLO within the phagocytic vacuole is a contributing factor to the immunodominance of the LLO 91-99 peptide. In Specific Aim I, studies are described that will determine if secretion of defined peptides within the phagocytic vacuole is a contributing factor to their immunodominance. For these studies, we will use L. monocytogenes mutants in which the anchor residue at position 2 within the Kd-binding nanomer peptide (normally a tyrosine) has been replaced by phenylalanine. The mutants retain the wildtype phenotype, yet following immunization with these strains, specific CTL are not stimulated to the mutant peptide sequence. We will use these mutants to deliver specific Listeria-derived peptides to the phagocytic vacuole or the cytoplasm of the L. monocytogenes infected cell in order to determine the influence of these initial locations on the subsequent CTL response. L. monocytogenes has been proposed as a vector to deliver candidate antigens and stimulate specific cell-mediated immunity. The value of vaccine vectors for delivery of candidate antigens depends in part on the ability to specifically stimulate the immune response in an environment of existing anti-vector immunity. In Specific Aim II, we will determine the utility of L. monocytogenes as a vaccine vector and assess the development of peptide specific immunity in animals that have defined levels of existing immunity to the vaccine vector. We will assess the development of peptide specific effector cell and memory cell responses. The results from these studies will guide strategies for the general development of novel vaccine carriers as well as to define the limits of their use within a population whose immunologic status to the vaccine carrier is unknown.

描述（改编自申请人的摘要）：对单核细胞增生李斯特氏菌的保护性免疫反应用于研究细胞介导的对细胞内细菌的免疫的一般特征。在BALB/C小鼠中，已经隔离了李斯特菌特异性CD8+ CTL，这些CTL受到KD的限制。李斯特氏蛋白O（LLO）的肽在吞噬液泡中分泌的分子和p60是细胞质中大量分泌的分子的p60，已被鉴定为CTL靶标。 CTL频率分析表明，LLO衍生的决定因素LLO 91-99是免疫主导的。我们假设在吞噬液泡内的LLO分泌是促成LLO 91-99肽免疫优势的一个因素。在特定的目标I中，描述了将确定吞噬液泡内定义的肽的分泌是否是导致其免疫降级的一个因素。在这些研究中，我们将使用单核细胞增生李斯特菌突变体，其中在Kd结合纳米剂肽（通常是酪氨酸）中，位于2的位置的锚固残基已被苯丙氨酸取代。突变体保留了野生型表型，但是在用这些菌株进行免疫后，特异性CTL并未被刺激到突变肽序列。我们将使用这些突变体将特定的李斯特菌衍生的肽传递到吞噬液泡或单核细胞增生李斯特菌感染细胞的细胞质，以确定这些初始位置对随后的CTL反应的影响。已提出单核细胞增生李斯特氏菌作为载体，以提供候选抗原并刺激特定的细胞介导的免疫。疫苗向量对候选抗原的交付的价值部分取决于在现有抗载体免疫环境中特异性刺激免疫反应的能力。在特定的目标II中，我们将确定单核细胞增生李斯特菌作为疫苗载体的效用，并评估肽特异性免疫的发展，这些动物定义了现有的对疫苗载体的免疫力。我们将评估肽特异性效应细胞和记忆细胞反应的发展。这些研究的结果将指导新型疫苗携带者的一般发展的策略，并定义其在人群中使用的限制，其对疫苗载体的免疫状态尚不清楚。