Immunomodulatory properties of umbilical cord blood

描述（由申请方提供）：已知胎儿和新生儿免疫系统不成熟，抗原刺激可引起耐受性而非效应子应答。外周血中的单核细胞分化为巨噬细胞和树突状细胞（DC），其驱动适应性免疫，并且它们还可能为T非依赖性B细胞应答提供细胞因子支持。我们最近在脐带血中鉴定了两种单核细胞（CD 14+），CD 36 hi和CD 36 low，并表明CD 36 hi单核细胞驱动调节性T（Treg）细胞的发育。使用特异性抑制剂的研究表明，诱导TGFAP需要TGF-？IL-10、视黄酸或芳香烃受体信号转导是不需要的。CD 36 h单核细胞表达TGF-β 1的潜伏形式。在细胞表面的复合物。我们假设婴儿的免疫抑制状态部分是由于这些免疫抑制性CD 36 hi单核细胞的优势，其促进Treg细胞的扩增。我们还假设，膜结合的TGF-？提供了生成TCLK所需的信令过程。在目标1，我们将研究的机制，TGF-？粘附在CD 36 hi单核细胞的细胞膜上。在目标2，我们将监测本地化的TGF-？受体复合物及其下游靶分子在CD 36 hi单核细胞诱导Foxp 3 + T细胞活化过程中的作用。这些研究的结果有望为理解胎儿/新生儿耐受性提供基础，并将有助于开发更安全和持久的免疫抑制。这项研究的结果也将有助于克服婴儿的免疫功能低下的状态，通过更有效的疫苗佐剂的组合，将废除婴儿的免疫抑制状态，以及提高他们的免疫力。

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.