ELDERLY IMMUNE RESPONSE TO PNEUMOCOCAL POLYSACCHARIDE

老年人对肺炎球菌多糖的免疫反应

• 批准号: 6097425
• 负责人: M.A. Julia WESTERINK
• 金额: $ 20.5万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6097425
• 关键词: B lymphocyte; SCID mouse; Streptococcus pneumoniae; Streptococcus pneumoniae vaccine; aging; antibacterial antibody; bacterial pneumonia; bacterial polysaccharides; bactericidal immunity; clinical research; complementary DNA; disease /disorder model; human old age (65+); human subject; human therapy evaluation; humoral immunity; immunoglobulin G; immunoglobulin genes; nonhuman therapy evaluation; nucleic acid sequence; vaccine development; young adult human (21-34)

Infection is one of the leading causes of morbidity and mortality in the elderly. Streptococcus pneumoniae is the organism most commonly isolated from elderly patients with pneumonia. Increased susceptibility to infections that occur in the elderly has been attributed to deteriorating health, decreased pulmonary function and a functional decline of the immune system. The immune system is unique in that it may be manipulated to achieve a desirable response. Studies in aged mice demonstrate both quantitative and qualitative changes in the immune response to T-independent type 2 (TI-2) antigens. Reports indicate age related loss of affinity, fine specificity and protective immunity are associated with a molecular shift in V gene usage and changes in cytokine profile. Studies of the in vivo immune response in elderly have been limited to vaccine efficacy studies and quantitative analysis of the magnitude and duration of the post-vaccination antibody response. The results of these studies suggest that despite adequate quantitative immune response the elderly show decreased vaccine efficacy. Current knowledge concerning the aging immune response to TI-2 antigens is mostly based on animal models and may not be applicable to humans. Human studies are fragmented and address quantitative and qualitative immune response as separate issues. We propose to study and characterize the immune response to S. pneumoniae capsular polysaccharide in the elderly. We will focus on both quantitative and qualitative changes in the immune response on molecular and functional levels. The quantitative immune response, isotype and IgG subclass, will be correlated with opsonophagocytic activity. We hypothesize that the discrepancy between the quantitative and qualitative immune response in the elderly results from altered V region sequence. We will characterize the immunoglobulin gene usage pattern and V-D-J joint diversity of the antibody response to pneumococcal polysaccharides (PPS) of serotypes 4 and 14 in elderly and young adults. This will be accomplished by gene family specific ELISA and by isolating single responding cells and determining the sequence of the V chains. Second, we propose to evaluate the influence of soluble regulatory factors on the aging immune response. The reconstituted SCID mouse model will be used to study the aging human B cell response to PPS 4 and 14 in a controlled cytokine environment allowing us to differentiate altered response intrinsic to the B cells versus altered responses secondary to environmental factors such as cytokines. The results of these studies will form the essential baseline for the rational development of vaccine and adjuvant strategies for the elderly.

感染是老年人发病和死亡的主要原因之一。 肺炎链球菌是从老年肺炎患者中最常分离到的微生物。老年人对感染的易感性增加归因于健康状况恶化、肺功能下降和免疫系统功能下降。 免疫系统的独特之处在于它可以被操纵以实现期望的反应。 对老年小鼠的研究表明，对 T 依赖性 2 型 (TI-2) 抗原的免疫反应发生了量和质的变化。 报告表明，与年龄相关的亲和力、精细特异性和保护性免疫的丧失与 V 基因使用的分子变化和细胞因子谱的变化有关。 老年人体内免疫反应的研究仅限于疫苗功效研究和疫苗接种后抗体反应的幅度和持续时间的定量分析。 这些研究的结果表明，尽管有足够的定量免疫反应，但老年人的疫苗功效却下降了。 目前有关 TI-2 抗原的衰老免疫反应的知识主要基于动物模型，可能不适用于人类。人类研究是分散的，并且将定量和定性免疫反应作为单独的问题来解决。 我们建议研究和表征老年人对肺炎链球菌荚膜多糖的免疫反应。 我们将重点关注分子和功能水平上免疫反应的量和质的变化。 定量免疫反应、同种型和 IgG 亚类将与调理吞噬活性相关。 我们假设老年人定量和定性免疫反应之间的差异是由于 V 区序列改变造成的。 我们将描述老年人和年轻人对血清型 4 和 14 肺炎球菌多糖 (PPS) 的抗体反应的免疫球蛋白基因使用模式和 V-D-J 联合多样性。 这将通过基因家族特异性 ELISA 以及分离单个响应细胞并确定 V 链的序列来完成。 其次，我们建议评估可溶性调节因子对衰老免疫反应的影响。 重建的 SCID 小鼠模型将用于在受控细胞因子环境中研究衰老的人类 B 细胞对 PPS 4 和 14 的反应，使我们能够区分 B 细胞固有的反应改变与细胞因子等环境因素继发的反应改变。这些研究的结果将成为合理开发老年人疫苗和辅助策略的重要基线。