Immunomodulatory properties of umbilical cord blood

脐带血的免疫调节特性

• 批准号: 8461805
• 负责人: MAKIO IWASHIMA
• 金额: $ 17.99万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461805
• 关键词: Adult; Animal Model; Antigens; Aryl Hydrocarbon Receptor; Autoantigens; B-Lymphocytes; Binding; Birth; Blood; CD14 gene; CD3 Antigens; CD36 gene; Cell Line; Cell membrane; Cell surface; Cells; Child; Communicable Diseases; Complex; Data; Dendritic Cells; Detection; Development; Employee Strikes; Generations; Hematopoietic stem cells; Human; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; Incidence; Infant; Inflammation; Interleukin-10; Lead; Life; Lymphocyte; Maintenance; Mediating; Membrane; Methods; Milk Proteins; Molecular; Monitor; Mononuclear; Mus; Neonatal; Outcome Study; Patients; Peptides; Pharmaceutical Preparations; Play; Population; Property; Receptor Activation; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signal Pathway; Signal Transduction; Source; Stream; Surface; System; T-Cell Activation; T-Lymphocyte; Testing; Time; Transforming Growth Factors; Transplantation; Tretinoin; Umbilical Cord Blood; Vaccine Adjuvant; Vaccines; adaptive immunity; aryl hydrocarbon receptor ligand; base; computerized data processing; cytokine; fetal; graft vs host disease; immunoregulation; inhibitor/antagonist; insight; macrophage; microorganism; monocyte; peripheral blood; prevent; public health relevance; receptor; response; success

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.

描述（由申请人提供）：已知胎儿和新生儿的免疫系统不成熟，抗原刺激可能引起耐受而不是效应反应。外周血中的单核细胞分化为巨噬细胞和树突状细胞 (DC)，从而驱动适应性免疫，并且它们还可能为不依赖于 T 的 B 细胞反应提供细胞因子支持。我们最近在脐带血中鉴定了两个单核细胞群 (CD14+)：CD36hi 和 CD36low，并表明 CD36hi 单核细胞驱动调节性 T (Treg) 细胞的发育。针对特定抑制剂的研究表明，Treg 的诱导需要 TGF-？信号传导，而不需要 IL-10、视黄酸或芳烃受体信号传导。 CD36h 单核细胞表达潜在形式的 TGF-β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 CD36hi 单核细胞占主导地位，它们促进了 Treg 细胞的扩增。我们还假设膜结合的 TGF-？提供生成 Tregs 所需的信号传导过程。在目标 1 中，我们将研究 TGF-？附着在 CD36hi 单核细胞的细胞膜上。在目标 2 中，我们将监测 TGF-？ CD36hi 单核细胞诱导 Foxp3+ Tregs 过程中受体复合物及其下游靶分子。这些研究的结果预计将为了解胎儿/新生儿的耐受性提供基础，并将有助于开发更安全、持久的免疫抑制。这项研究的结果还将有助于通过组合更有效的疫苗佐剂来克服婴儿的免疫低下状态，从而消除婴儿的免疫抑制状态并增强他们的免疫力。