NEONATAL TH1/TH2 PRIMARY AND MEMORY CELL DEVELOPMENT

新生儿 TH1/TH2 原代细胞和记忆细胞发育

基本信息

批准号：
6511083
负责人：
REBECCA D ADKINS
金额：
$ 30万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6511083
关键词：
antigen presenting cell cellular immunity cytokine developmental immunology helper T lymphocyte immature animal immunologic memory laboratory mouse passive immunization protein biosynthesis

项目摘要

Immune responses in neonates are often poor. As a result, neonates succumb to infections and diseases which seldom affect adults. The deficient immunity of neonates is associated with poor Th1 function. Because Th1 function is centrally important in cellular immune responses, a clear understanding of the dysregulation of Th1 lineage cells in neonates must be achieved to devise strategies leading to the prevention and treatment of disease in early life. This proposal aims to identify the cellular and biochemical mechanisms governing poor Th1 function in neonates in situ. Specific Aims 1 and 2 focus on the inability of neonates to develop mature Th1 memory responses. Specific Aim 3 will concentrate on the failure of neonates to generate enhanced primary Th1 responses when antigen is delivered in adjuvant. Specific Aim 1 will test the hypothesis that the inability to generate Th1 dominant memory is due to developmental immaturity in both neonatal T cells and non-T cells. This will be tested by physically separating the two compartments in chimeric mice in vivo: the capacity of neonatal T cells to develop mature Th1 memory in adoptive adult TCRbeta-deficient hosts will be assessed; conversely, the capacity of neonatal TCRbeta-deficient hosts to support mature Th1 memory development by adult T cells will be examined. The ability of neonatal T cells to develop mature Th1 memory when antigen is delivered to intact neonates by mature adult dendritic cells will also be investigated. Lastly, whether neonatal transgenic T cells bearing mature, adult-derived TCR are able to achieve mature Th1 memory in situ, in adoptively transferred normal neonates, will be tested. Specific Aim 2 will test the hypothesis that poor Th1 memory results from the preferential survival of Th2 cells due to developmental immaturity in the endogenous cytokine milieu. The frequencies of antigen-specific Th1 vs Th2 cells in neonates and adults will be measured following primary and secondary immunization. The antigen-driven production of proinflammatory cytokines known to modulate T cell development, function, and survival will be compared in immunized neonates and adults. Lastly, the capacity of exogenously administered IL-2 and/or proinflammatory cytokines to influence Th1 memory development in neonates will be assessed. Specific Aim 3 will test the hypothesis that the failure of neonates to respond to adjuvant with increased primary Th1 activity is due to limited function within the APC compartment. First, the contributions of the innate properties of the neonatal T cell and non-T cell compartments to poor responsiveness to adjuvant will be assessed: neonatal T cells will be transferred to adult TCRbeta-deficient hosts, and vice versa, and primary Th1 responses to antigen in adjuvant will be assessed. Second, the adjuvant-induced upregulation of two major Th1-promoting cytokines, IL-12 and IL- 18, will be compared in intact neonates and adults. Finally, the capacity of coadministered IL-12 and IL-18 to enhance adjuvant- induced primary Th1 function in neonates will be tested.

新生儿的免疫反应通常很差。因此，新生儿会死于很少影响成人的感染和疾病。新生儿免疫力低下与Th1功能较差有关。由于 Th1 功能在细胞免疫反应中至关重要，因此必须清楚地了解新生儿中 Th1 谱系细胞的失调，以制定预防和治疗生命早期疾病的策略。该提案旨在原位确定控制新生儿 Th1 功能不良的细胞和生化机制。具体目标 1 和 2 重点关注新生儿无法形成成熟的 Th1 记忆反应。具体目标 3 将集中于当在佐剂中递送抗原时，新生儿未能产生增强的初级 Th1 反应。具体目标 1 将检验以下假设：无法生成 Th1 显性记忆是由于新生儿 T 细胞和非 T 细胞发育不成熟所致。这将通过在体内物理分离嵌合小鼠的两个区室来进行测试：将评估新生 T 细胞在领养的 TCRbeta 缺陷成年宿主中形成成熟 Th1 记忆的能力；相反，将检查新生儿 TCRbeta 缺陷宿主支持成体 T 细胞成熟 Th1 记忆发育的能力。当成熟的成年树突细胞将抗原传递给完整的新生儿时，新生儿 T 细胞形成成熟 Th1 记忆的能力也将受到研究。最后，将测试携带成熟、成人来源的 TCR 的新生儿转基因 T 细胞是否能够在过继转移的正常新生儿中原位实现成熟的 Th1 记忆。具体目标 2 将检验以下假设：由于内源性细胞因子环境中发育不成熟，Th2 细胞优先存活，从而导致 Th1 记忆不良。将在初次和二次免疫后测量新生儿和成人中抗原特异性 Th1 与 Th2 细胞的频率。已知可调节 T 细胞发育、功能和存活的抗原驱动促炎细胞因子的产生将在免疫新生儿和成人中进行比较。最后，将评估外源性给予 IL-2 和/或促炎细胞因子影响新生儿 Th1 记忆发育的能力。具体目标 3 将检验以下假设：新生儿未能对初级 Th1 活性增加的佐剂做出反应是由于 APC 隔室内的功能有限。首先，将评估新生儿 T 细胞和非 T 细胞区室的先天特性对佐剂反应性差的贡献：新生儿 T 细胞将被转移到成人 TCRbeta 缺陷宿主，反之亦然，并且初级 Th1 反应将评估佐剂中的抗原。其次，将在完整新生儿和成人中比较佐剂诱导的两种主要 Th1 促进细胞因子 IL-12 和 IL-18 的上调。最后，将测试联合施用 IL-12 和 IL-18 增强新生儿佐剂诱导的初级 Th1 功能的能力。