Induction of polysaccharide vaccine responses in the young by interleukin-7

白细胞介素7诱导年轻人多糖疫苗反应

• 批准号: 8786494
• 负责人: KISHORE R ALUGUPALLI
• 金额: $ 7.75万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786494
• 关键词: Adult; Antibodies; Antibody Response; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Binding Proteins; Borrelia; CD34 gene; Cell Count; Cells; Characteristics; Child; Cloaca Chamber; Communicable Diseases; Complement Factor H; Data; Development; Dextrans; Encapsulated; Enterobacter cloacae; Exhibits; Ficoll; Frequencies; Health; Hematopoietic stem cells; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunization; Impairment; Individual; Infant; Infection; Interleukin-7; Kinetics; Lead; Life; Lymphocyte; Mature B-Lymphocyte; Measures; Memory B-Lymphocyte; Molecular; Morbidity - disease rate; Mus; Neonatal; Phenotype; Plasma Cells; Play; Polysaccharides; Receptors, Antigen, B-Cell; Role; Salmonella typhi; Signal Transduction; Streptococcus pneumoniae; Stromal Cells; Supplementation; Surface Antigens; T-Lymphocyte; Transgenic Mice; Transgenic Organisms; Translating; Umbilical Cord Blood; Vaccination; Vaccines; acquired immunodeficiency; base; infant morbidity/mortality; mortality; mouse model; novel; novel strategies; pathogen; reconstitution; response; vaccine response

DESCRIPTION (provided by applicant): Antibody responses to classical T cell-independent (TI) antigens such as bacterial capsular polysaccharides are highly protective, and play a critical role in controlling a number of clinically important infections. For reasons that remain poorly understood young children cannot mount antibody responses to TI antigens and as a consequence are much more prone to suffer from life-threatening infections, particularly from encapsulated bacterial pathogens. As with young children, young mice respond poorly to polysaccharide antigens, while human adults as well as adult mice can mount a very efficient response to polysaccharide antigens. B1b lymphocytes are a subset of mature B cells that increases in number in response to a variety of TI antigens including type 3 polysaccharide of Streptococcus pneumoniae (PPS3), ¿1,3 dextran of Enterobacter cloacae, Vi polysaccharide of Salmonella typhi and Factor H binding protein A, a surface antigen of Borrelia hermsii. Furthermore, these cells generate rapid primary antibody as well as long-lasting memory B cell responses. Despite having B1b cells, young mice are impaired in responding to polysaccharide antigens, suggesting that B cells in the young are distinct from those in adults. Since B lymphopoeisis early in life is largely IL-7- independent, while in adults it is IL-7-dependent, we hypothesize that B cells developed in the presence of IL-7 are required for generating anti-polysaccharide antibody responses. In support of this, we found that despite having B1b cells, young wildtype, adult IL-7-/- or adult IL-7R¿-/- mice are severely impaired in responding to classical TI antigens such as 4-hydroxy-3-nitrophenyl-acetyl-Ficoll (NP-Ficoll), bacterial dextran and PPS vaccine, and do not survive S. pneumoniae challenge after PPS immunization. Furthermore, we found that transgenic expression of IL-7 promotes the anti-PPS response in young and confers protective immunity to S. pneumoniae. These data support the hypothesis that IL-7-dependent B cells play a crucial role in generating TI humoral immunity. To translate these findings to human infants we have utilized neonatal NOD/SCID/?cnull mice engrafted with human umbilical cord blood CD34+ hematopoietic stem cells to create a "Human Immune System" mouse (HISmouse) model. We have found that these HISmice generate several subsets of B cells including B1 cells and the majority of them exhibit an immature B cell phenotype. Moreover, just as young children, HISmice responded poorly to PPS and sub-optimally to B. hermsii. Since IL-7 is produced mainly by non-hematopoietic stromal cells, and murine IL-7 is poor stimulator of human lymphocyte development, this impairment could be due to the lack of human IL-7-driven B cells in HISmice. In support of this we found that supplementation of HISmice with human IL-7 dramatically increases humoral responses to B. hermsii. The aims outlined in this proposal seek to: 1) determine whether IL-7 increases the number of polysaccharide- specific B1b cells; and 2) determine whether the B1b cells generated in the presence or absence of IL-7 are qualitatively different.

描述（由申请人提供）：对经典 T 细胞非依赖性 (TI) 抗原（例如细菌荚膜多糖）的抗体反应具有高度保护性，并发挥关键作用 在控制许多临床上重要的感染中发挥作用。由于目前尚不清楚的原因，幼儿无法对 TI 抗原产生抗体反应，因此更容易遭受危及生命的感染，特别是来自封装的细菌病原体的感染。与幼儿一样，年幼的小鼠对多糖抗原的反应很差，而成年人和成年小鼠可以对多糖抗原产生非常有效的反应。 B1b 淋巴细胞是成熟 B 细胞的一个子集，其数量会随着各种 TI 抗原的增加而增加，这些抗原包括肺炎链球菌 (PPS3) 的 3 型多糖、阴沟肠杆菌的 1,3 葡聚糖、伤寒沙门氏菌的 Vi 多糖和疏螺旋体表面抗原 H 因子结合蛋白 A 赫姆斯。此外，这些细胞可产生快速的一抗以及持久的记忆 B 细胞反应。尽管拥有 B1b 细胞，但年轻小鼠对多糖抗原的反应能力受损，这表明年轻小鼠的 B 细胞与成年小鼠的不同。由于生命早期的 B 淋巴细胞生成很大程度上不依赖于 IL-7，而成人中的 B 淋巴细胞生成则依赖于 IL-7，因此我们假设在 IL-7 存在下发育的 B 细胞是产生抗多糖抗体反应所必需的。为了支持这一点，我们发现，尽管有 B1b 细胞，但年轻的野生型、成年 IL-7-/- 或成年 IL-7R¿-/- 小鼠对经典 TI 抗原（如 4-羟基-3-硝基苯基-乙酰基聚蔗糖 (NP-Ficoll)、细菌葡聚糖）的反应严重受损 和 PPS 疫苗，并且在 PPS 免疫后不能在肺炎链球菌攻击中存活。此外，我们发现 IL-7 的转基因表达可促进年轻人的抗 PPS 反应，并赋予对肺炎链球菌的保护性免疫力。这些数据支持这样的假设：IL-7 依赖性 B 细胞在产生 TI 体液免疫中发挥着至关重要的作用。为了将这些发现转化为人类婴儿，我们利用移植了人脐带血 CD34+ 造血干细胞的新生 NOD/SCID/?cnull 小鼠来创建“人类免疫系统”小鼠 (HISmouse) 模型。我们发现这些 HISmice 产生了几个 B 细胞亚群，包括 B1 细胞，其中大多数表现出不成熟的 B 细胞表型。此外，就像年幼的孩子一样，HISmice 对 PPS 的反应很差，对赫氏芽孢杆菌的反应也不佳。由于 IL-7 主要由非造血基质细胞产生，而鼠 IL-7 对人类淋巴细胞发育的刺激作用较差，因此这种损害可能是由于 HISmice 中缺乏人类 IL-7 驱动的 B 细胞。为了支持这一点，我们发现向 HISmice 补充人 IL-7 会显着增加对赫氏芽孢杆菌的体液反应。该提案概述的目标旨在：1) 确定 IL-7 是否增加多糖特异性 B1b 细胞的数量； 2)确定在存在或不存在IL-7的情况下产生的B1b细胞是否有质量上的不同。