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（由适用提供）：传染病的婴儿死亡率导致全世界数百万六个月以下的婴儿死亡。婴儿的免疫抑制系统受到抑制，这使其高度容易受到感染的影响，并限制了其免疫抑制以保护和挽救生命的疫苗。外周血中的单核细胞与巨噬细胞和树突状细胞（DC）区分开，这些细胞驱动适应性免疫组织化学，它们也可能为T非依赖性B细胞反应提供细胞因子支持。我们最近确定了脐带血，CD36HI和CD36LO中的两个单核细胞（CD14+）群，并表明CD36HI单核细胞驱动了调节t（Treg）细胞的发育。我们假设婴儿的免疫抑制状态部分归因于这些免疫抑制性CD36HI单核细胞的占主导地位，从而促进Treg细胞的扩张。我们还假设在婴儿期，这些细胞在AIM 1中，我们将检查CD36HI单核细胞发起的先天免疫调查剂，以确定婴儿抑制单核细胞损害婴儿的先天免疫力的程度。 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 influences Treg cells;在AIM 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激动剂对这些单核细胞的处理是否可以诱导这些细胞以支持Ti B细胞反应。这些研究的结果预计将通过更有效的疫苗调节器的结合来克服婴儿的免疫抑制状态，从而消除婴儿的免疫抑制状态并增强其免疫力。婴儿的主要缺乏是他们无法产生对多糖抗原（例如免疫学链球菌肺炎）所需的Ti B细胞反应，我们希望这些结果将确定诱导婴儿产生这种挽救生命的免疫反应的手段。