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

描述(由申请人提供)：对经典T细胞非依赖(TI)抗原的抗体反应，如细菌囊多糖，具有高度的保护性，并在 在控制一些临床上重要的感染方面发挥作用。由于尚不清楚的原因，幼儿不能对TI抗原产生抗体反应，因此更容易受到威胁生命的感染，特别是来自被包裹的细菌病原体的感染。与幼儿一样，幼鼠对多糖类抗原的反应很差，而人类成年人和成年小鼠对多糖类抗原的反应非常有效。B1B淋巴细胞是成熟B细胞的一个亚群，在多种TI抗原的作用下数量增加，包括肺炎链球菌3型多糖(PPS3)、阴沟肠杆菌的1，3-葡聚糖、伤寒沙门氏菌的Vi多糖和赫氏疏螺旋体的表面抗原-H因子结合蛋白A。此外，这些细胞产生快速的初级抗体以及持久的记忆B细胞反应。尽管小鼠有B1B细胞，但幼鼠对多糖抗原的反应受到损害，这表明幼鼠的B细胞与成人的B细胞是不同的。由于生命早期的B淋巴细胞生成在很大程度上依赖于IL-7，而在成年人中它是依赖于IL-7的，因此我们假设在存在IL-7的情况下发育的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，年轻的野生型、成年的IL-7-/-或成年的IL-7R-/-小鼠对经典的TI抗原如4-羟基-3-硝基苯乙酰-Ficoll(NP-Ficoll)、细菌右旋糖苷的反应严重受损 和PPS疫苗，并在PPS免疫后不能存活肺炎链球菌。此外，我们还发现，IL-7的转基因表达促进了幼虫的抗PPS反应，并对肺炎链球菌产生了保护性免疫。这些数据支持依赖IL-7的B细胞在产生TI体液免疫中起关键作用的假说。为了将这些发现转化到人类婴儿身上，我们利用新生NOD/SCID/？Cnul小鼠移植了人脐血CD34+造血干细胞来创建“人类免疫系统”小鼠(HIS小鼠)模型。我们发现，这些HIS小鼠产生了包括B1细胞在内的几个B细胞亚群，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，HIS小鼠对PPS的反应很差，对B.hermsii的反应次之。由于IL-7主要由非造血基质细胞产生，而小鼠IL-7对人类淋巴细胞发育的刺激作用较差，这种损害可能是由于HIS小鼠缺乏人IL-7驱动的B细胞所致。为了支持这一点，我们发现，给HIS小鼠补充人IL-7显著增加了对赫氏杆菌的体液反应。这项提案中概述的目标是：1)确定IL-7是否增加多糖特异性B1B细胞的数量；以及2)确定在有或没有IL-7的情况下产生的B1B细胞是否有质的不同。

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.