Human immune system layering and the neonatal response to vaccines

人体免疫系统分层和新生儿对疫苗的反应

• 批准号: 8091879
• 负责人: JOSEPH M MCCUNE
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091879
• 关键词: Address; Adult; Antigens; Birds; Birth; Blood Banks; Blood specimen; Bone Marrow; Cell Lineage; Cell physiology; Cells; Child health care; Childhood; Clinical Sciences; Collaborations; Cytotoxic T-Lymphocytes; Data; Development; Disease; Exhibits; Exposure to; Fetal Liver; Fetus; General Hospitals; Growth; Hematopoietic; Hepatitis B Vaccination; Human; Immune response; Immune system; Immunization; Infant; Infection; Institutes; Lymphocyte; Modality; Mononuclear; Mus; Neonatal; Newborn Infant; Normal Range; Physiological; Population; Predisposition; Prospective Studies; Protocols documentation; Public Health; Research; Sampling; San Francisco; Staging; Stem cells; System; T-Lymphocyte; Time; Translational Research; Umbilical Cord Blood; University of Texas M D Anderson Cancer Center; Vaccination; Vaccines; Variant; fetal; in utero; neonate; neutralizing antibody; research study; response; stem

DESCRIPTION (provided by applicant): The development of the mammalian immune system is typically thought to occur in a linear fashion, from immaturity to maturity as a function of antigen exposure. Previous findings in birds and in mice, however, indicate that this view is oversimplified. Thus, in these species, the developing immune system appears to be "layered" in a manner that is independent of antigen exposure, beginning as a multilineage fetal system that is replaced by an anatomically and biologically distinct multilineage system after birth. If so, then developmentally ordered and unique hematopoietic stem/progenitor cells (HSPC) could give rise to distinct lymphocyte lineages at different stages of development. In ongoing experiments, we have found that such immune system "layering" occurs in humans. Our preliminary data show that a vigorous human fetal immune response to exogenous antigens can be actively suppressed by antigen-specific Tregs, that these fetal Tregs are derived from a fetal-specific lineage of T cells, and that this lineage is generated by an HSPC that is distinct from that found in adults. These data suggest that the human immune system is comprised of two distinct waves: one generated from a "fetal" HSPC that exists in utero in the fetal liver and bone marrow, and another generated from a superseding "adult" HSPC that resides in the bone marrow at later time points. The former gives rise to an immune system that is prone to deliver a tolerogenic response to foreign antigens. The latter gives rise to an immune system that is more likely to generate an immunoreactive response (e.g., one including cytotoxic T cells and neutralizing antibodies). Given these findings, we hypothesize that physiologic layering of immune system ontogeny leads to a normal range in the ratio of fetal- to adult-type T cells at birth, with some neonates exhibiting a higher fraction of fetal T cells than others; and that those with a high ratio of fetal/adult T cells will generate predominant Th2 responses to routine childhood immunizations. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to determine the normal range of fetal to adult T cells in the umbilical cord blood of the full term neonate; and (2) to determine whether those full term neonates with a high ratio of fetal/adult T cells are more likely to generate a Th2-polarized immune response to routine childhood vaccines. Should this exploratory study reveal normal variation in the ratio of fetal to adult T cells at birth and should such variation be directly related to a Th2 skew after childhood vaccination, modalities aimed at changing this ratio more towards the adult lineage at birth may provide benefit to a substantial number of newborns. PUBLIC HEALTH RELEVANCE: These exploratory studies are relevant to public health for two reasons. First, they may provide proof-of- concept evidence for the existence of a range in the extent of immune system "layering" in human neonates. Secondly, they may demonstrate that this range is itself related to (and possibly causal of) differences in the ability of neonates to withstand infections and to respond to vaccines.

描述（由申请人提供）：通常认为哺乳动物免疫系统的发展是以线性方式发生的，从不成熟到成熟作为抗原暴露的函数。然而，先前在鸟类和小鼠中的发现表明这种观点过于简单。因此，在这些物种中，发育中的免疫系统似乎以独立于抗原暴露的方式“分层”，从出生后被解剖和生物学上不同的多素养系统所取代的多节胎胎儿系统开始。如果是这样，那么发育有序的独特的造血干/祖细胞（HSPC）可能会在不同发育阶段引起独特的淋巴细胞谱系。在正在进行的实验中，我们发现这种免疫系统“分层”发生在人类中。我们的初步数据表明，可以通过抗原特异性Treg来积极抑制对外源抗原的剧烈胎儿免疫反应，这些胎儿Treg是从T细胞的胎儿特异性谱系中得出的，并且该谱系是由在成年人中发现的HSPC产生的。这些数据表明，人类免疫系统由两个不同的波动组成：一种由胎儿肝脏和骨髓中子宫中存在的“胎儿” HSPC产生，另一个是由后来时间点位于骨髓中的取代的“成人” HSPC产生的。前者产生的免疫系统很容易对外国抗原产生耐受性反应。后者产生一种免疫系统，该系统更可能产生免疫反应反应（例如，包括细胞毒性T细胞和中和抗体）。鉴于这些发现，我们假设免疫系统的生理分层导致出生时胎儿与成人型T细胞的比率正常，其中一些新生儿比其他新生儿表现出更高的胎儿T细胞分数。胎儿/成人T细胞比率高的人会产生对常规儿童免疫的主要反应。这些假设将在以下特定目的的实验中解决：（1）确定完整术语新生儿的脐带血液中胎儿对成年T细胞的正常范围； （2）确定那些胎儿/成人T细胞比率高的新术语是对常规儿童疫苗的Th2极化免疫反应的可能性。如果这项探索性研究揭示了出生时胎儿与成人T细胞比率正常的变化，并且如果这种变异与儿童疫苗接种后Th2偏斜直接相关，则旨在将这种比率更改为出生时成年谱系的方式可能会为大量新生儿提供益处。 公共卫生相关性：这些探索性研究与公共卫生有关，原因有两个。首先，他们可以为人类新生儿“分层”的范围存在范围的存在提供证明证据。其次，他们可以证明该范围本身与新生儿承受感染和对疫苗反应的能力的差异（可能以及可能因果关系）有关。