Monocyte Regulation of Infant Immune Responses

描述(申请人提供)：传染病导致的婴儿死亡在全球范围内造成数百万6个月以下婴儿的死亡。婴儿的免疫系统受到抑制，这使他们非常容易受到感染，并限制了他们对保护性和救命疫苗的免疫反应。外周血中的单核细胞分化为巨噬细胞和树突状细胞(DC)，它们驱动获得性免疫，也可能为T非依赖性B细胞反应提供细胞因子支持。我们最近在脐带血中发现了两类单核细胞(CD14+)，CD36hi和CD36lo，并发现CD36hi单核细胞驱动调节性T(Treg)细胞的发育。我们推测，婴儿的免疫抑制状态部分是由于这些免疫抑制CD36hi单核细胞占优势，从而促进Treg细胞的扩张。我们还假设，在婴儿期，这些细胞对先天免疫信号的反应很差，无法支持T非依赖性(TI)B细胞反应。在目标1中，我们将检测CD36hi单核细胞启动的先天免疫反应，以确定免疫抑制单核细胞对婴儿先天免疫的损害程度。在目标2中，我们将监测CD36hi单核细胞在婴儿期和整个儿童期的数量和功能的变化，并确定是否可以通过病原体识别受体(PRR)激动剂刺激它们或通过阻断CD36与TSP1的结合来将它们从促进Treg细胞转化为效应T细胞；TSP1是诱导Treg细胞的潜在转化生长因子-β的激活剂；在目标3中，我们将确定CD36hi单核细胞是否无法支持TI B细胞的反应，并确定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细胞的反应。这些研究的结果有望为通过组合更有效的疫苗佐剂来克服婴儿的免疫抑制状态提供基础，这些佐剂将消除婴儿的免疫抑制状态并增强他们的免疫力。婴儿的一个主要缺陷是他们不能产生对多糖类抗原的TI B细胞反应，这是对链球菌肺炎免疫所必需的，我们预计结果将确定诱导婴儿产生这种拯救生命的免疫反应的方法。

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.