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: 8638380
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638380
• 关键词: Adult; Antibodies; Antibody Formation; 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; 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; dextran; infant morbidity/mortality; mortality; mouse model; novel; novel strategies; pathogen; public health relevance; reconstitution; response

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.

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，在控制许多临床重要感染方面发挥着关键作用。为了 幼儿无法对 TI 抗原产生抗体反应的原因仍知之甚少，并且 结果是更容易遭受危及生命的感染，特别是来自包膜的感染 细菌病原体。与幼儿一样，年幼的小鼠对多糖抗原的反应较差，而 成人以及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 抗原的反应而增加 包括肺炎链球菌3型多糖（PPS3）、阴沟肠杆菌的1,3葡聚糖、 Vi 伤寒沙门氏菌的多糖和H因子结合蛋白A，赫氏疏螺旋体的表面抗原。 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。 尽管有 B1b 细胞，但年轻小鼠对多糖抗原的反应受损，这表明 年轻人的 B 细胞与成人的不同。由于生命早期的 B 淋巴细胞生成主要是 IL-7- 独立的，而在成人中它是 IL-7 依赖性的，我们假设 B 细胞在 IL-7 存在的情况下发育 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 具有 B1b 细胞的年轻野生型小鼠、成年 IL-7-/- 或成年 IL-7R¿-/- 小鼠对 B1b 细胞的反应严重受损 经典 TI 抗原，例如 4-羟基-3-硝基苯基-乙酰基-聚蔗糖 (NP-Ficoll)、细菌葡聚糖和 PPS 疫苗，并且在 PPS 免疫后不能存活于肺炎链球菌攻击。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，并赋予对金黄色葡萄球菌的保护性免疫力。 肺炎杆菌。这些数据支持这样的假设：IL-7 依赖性 B 细胞在产生 TI 中发挥着至关重要的作用 体液免疫。为了将这些发现转化为人类婴儿，我们利用了新生儿 NOD/SCID/¿cnull 小鼠移植人脐带血CD34+造血干细胞，打造“人类免疫细胞” System”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。而且，同样年轻 对于儿童，HISmice 对 PPS 的反应较差，对 B. Hermsii 的反应也不佳。由于 IL-7 主要由 非造血基质细胞，而鼠 IL-7 对人类淋巴细胞发育的刺激作用较差，因此 损伤可能是由于 HISmice 中缺乏人类 IL-7 驱动的 B 细胞所致。为了支持这一点，我们发现 给 HISmice 补充人 IL-7 可以显着增加对赫氏芽孢杆菌的体液反应。这 本提案概述的目标旨在：1) 确定 IL-7 是否增加多糖的数量 特定的 B1b 细胞； 2) 确定在存在或不存在 IL-7 的情况下生成的 B1b 细胞是否是 质不同。