Immunomodulatory properties of umbilical cord blood

描述(申请人提供)：已知胎儿和新生儿的免疫系统是不成熟的，抗原刺激可以引起耐受而不是效应者反应。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CD36low，并表明CD36hi单核细胞驱动调节性T(Treg)细胞的发育。使用特定抑制剂的研究表明，Tregs的诱导需要转化生长因子？IL-10、维甲酸或芳烃受体信号转导不是必需的。CD36h单核细胞表达潜伏型转化生长因子-β。细胞表面的复合体。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。我们还假设膜结合的转化生长因子？提供生成Tregs所需的信令过程。在目标1中，我们将研究转化生长因子-β？附着在CD36hi单核细胞的细胞膜上。在目标2中，我们将监测转化生长因子-β的定位。CD36hi单核细胞诱导Foxp3+Tregs过程中的受体复合体及其下游靶分子这些研究的结果有望为了解胎儿/新生儿的耐受性提供基础，并将有助于开发更安全和持久的免疫抑制。这项研究的结果还将通过组合更有效的疫苗佐剂来帮助克服婴儿的免疫抑制状态，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。

DESCRIPTION (provided by applicant): Fetal and neonatal immune system is known to be immature and antigen stimulation can cause tolerance rather than effector responses. 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 CD36low and shown that the CD36hi monocytes drive development of regulatory T (Treg) cells. Study suing specific inhibitors showed that induction of Tregs require TGF-? signaling while IL-10, retinoic acid, or aryl hydrocarbon receptor signaling is not required. CD36h monocytes express the latent form of TGF-? complex on the cell surface. 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 membrane-bound TGF-? provides a signaling process required for generation of Tregs. In Aim 1, we will examine the mechanism by which TGF-? is attached to the cell membrane of CD36hi monocytes. In Aim 2, we will monitor localization of TGF-? receptor complex and its down stream target molecules during induction of Foxp3+ Tregs by CD36hi monocytes. Results from these studies are expected to provide a basis for understanding fetal/neonatal tolerance and will help developing safer and long lasting immunesuppression. The outcomes of this study will also help overcoming the immunocompromised 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.