Monocyte Regulation of Infant Immune Responses

婴儿免疫反应的单核细胞调节

• 批准号: 8691718
• 负责人: MAKIO IWASHIMA
• 金额: $ 42.98万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691718
• 关键词: Adjuvant; Adult; Age; Age-Months; Agonist; Antigens; B-Lymphocytes; Binding; Birth; Blood; CD14 gene; CD3 Antigens; CD36 gene; Cells; Cessation of life; Child; Child Support; Childhood; Communicable Diseases; Data; Dendritic Cells; Development; Elderly; Employee Strikes; Frequencies; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; Infant; Infant Mortality; Infection; Inflammation; Lead; Life; Lymphocyte; Monitor; Mononuclear; Natural Immunity; Neonatal; Phenotype; Plasma; Pneumonia; Polysaccharides; Population; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Signal Transduction; Stimulus; T-Lymphocyte; Testing; Thrombospondin 1; Toddler; Transforming Growth Factors; Umbilical Cord Blood; Vaccine Adjuvant; Vaccines; adaptive immunity; aged; base; cytokine; high risk infant; infancy; macrophage; microorganism; monocyte; mortality; neonate; pathogen; peripheral blood; prevent; receptor; response; tool

DESCRIPTION (provided by applicant): Infant mortality from infectious diseases results in millions of deaths worldwide in infants younger than six months of age. Infants have a suppressed immune system which makes them highly vulnerable to infections and limits their immune responses to protective and life-saving vaccines. Monocytes in peripheral blood differentiate to macrophages and dendritic cells (DC) which drive adaptive immunity, and they also likely provide cytokine support for T-independent B cell responses. We have recently identified two populations of monocytes (CD14+) in cord blood, CD36hi and CD36lo and shown that the CD36hi monocytes drive development of regulatory T (Treg) cells. We hypothesize that the immunosuppressive state of infants is due in part to the predominance of these immunosuppressive CD36hi monocytes which promote expansion of Treg cells. We also hypothesize that during infancy, these cells respond poorly to innate immune signals and are unable to support T-independent (TI) B cell responses. In Aim 1, we will examine the innate immune responses initiated by CD36hi monocytes to determine the extent to which innate immunity in infants is compromised by the immunosuppressive monocytes. In Aim 2, we will monitor changes in the number and function of CD36hi monocytes during infancy and throughout childhood, and determine if they can be converted from promoting Treg cells to effector T cells by stimulating them with pathogen recognition receptor (PRR) agonists or by blocking binding of CD36 to TSP1, an activator of latent TGF-¿ which induces Treg cells; and in Aim 3, we will determine if the CD36hi monocytes are unable to support TI B cell responses and determine if treatment of these monocytes with PPR agonists can induce these cells to support TI B cell responses. Results from these studies are expected to provide a basis for overcoming the immunosuppressive state of infants by a combination of more effective vaccine adjuvants that will abrogate the immunosuppressive state of infants as well as enhance their immunity. A major deficiency of infants is their inability to generate TI B cell responses to polysaccharide antigens such as is required for immunity to Streptococcal pneumonia, and we expect the results will identify the means to induce infants to generate such life-saving immune responses.

描述（由申请人提供）：传染病导致的婴儿死亡率导致全球数以百万计的六个月以下婴儿死亡。婴儿的免疫系统受到抑制，这使他们极易受到感染，并限制了他们对保护性和生命的免疫反应。外周血中的单核细胞分化为巨噬细胞和树突细胞 (DC)，从而驱动适应性免疫，并且它们也可能为 T 依赖性 B 细胞反应提供细胞因子支持。我们最近发现了两个单核细胞群 (CD14+)。我们对脐带血中的 CD36hi 和 CD36lo 进行了研究，结果表明 CD36hi 单核细胞驱动调节性 T (Treg) 细胞的发育，我们发现婴儿的免疫抑制状态部分是由于这些免疫抑制性 CD36hi 细胞占主导地位，这些细胞促进了 Treg 细胞的扩增。我们还承认，在婴儿期，这些细胞对先天免疫信号的反应很差，并且无法支持 T 独立 (TI) B 细胞反应。 1，我们将检查 CD36hi 单核细胞发起的先天免疫反应，以确定婴儿先天免疫受到免疫抑制单核细胞损害的程度。在目标 2 中，我们将监测婴儿期和整个过程中 CD36hi 单核细胞数量和功能的变化。并确定是否可以通过用病原体识别受体 (PRR) 激动剂刺激 Treg 细胞或通过阻断 CD36 与TSP1，潜在 TGF-¿ 的激活剂其诱导 Treg 细胞；在目标 3 中，我们将确定 CD36hi 单核细胞是否无法支持 TI B 细胞反应，并确定用 PPR 激动剂处理这些单核细胞是否可以诱导这些细胞支持 TI B 细胞反应。有望通过组合更有效的疫苗佐剂来消除婴儿的免疫抑制状态并增强其免疫抑制状态，从而为克服婴儿的免疫抑制状态提供基础。婴儿的一个主要缺陷是他们无法产生对多糖抗原的 TI B 细胞反应，例如对链球菌肺炎的免疫所需的反应，我们期望结果将确定诱导婴儿产生这种挽救生命的免疫反应的方法。