The Role of Decidual Innate Immunity in the Pathogenesis of Preeclampsia

蜕膜先天免疫在先兆子痫发病机制中的作用

• 批准号: 8242882
• 负责人: SE-TE JOSEPH HUANG
• 金额: $ 27.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242882
• 关键词: A Mouse; Accounting; Affect; Allogenic; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Basement membrane; Biological Assay; Blood flow; CD80 gene; Cell Culture Techniques; Cells; Coculture Techniques; Complication; Conditioned Culture Media; Decidua; Decidual Cell; Dendritic Cells; Development; Disease; Embryo; Endometrial; Endothelial Cells; Equilibrium; Excision; FCGR3B gene; Family; First Pregnancy Trimester; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Helper-Inducer T-Lymphocyte; Human; Hypertension; ICAM1 gene; ITGB2 gene; Immune; Immune Tolerance; Immune response; Immune system; Implant; In Vitro; Incubated; Inflammatory; Interferons; Interleukin-1; Interleukin-1 beta; Interleukin-12; Interleukin-6; Invaded; Kidney; Lead; Leukocytes; Link; MHC Class I Genes; Macrophage Colony-Stimulating Factor; Major Histocompatibility Complex; Mediating; Migration Assay; Morbidity - disease rate; Mus; Natural Immunity; Natural Killer Cells; Nitric Oxide; Output; Pathogenesis; Perinatal; Peripheral Blood Mononuclear Cell; Play; Population; Pre-Eclampsia; Pregnancy; Prevention therapy; Proteinuria; Recruitment Activity; Relative (related person); Resistance; Role; Septic Toxemia; Site; Social Welfare; Societies; Spiral Artery of the Endometrium; Stress; Surface; Symptoms; System; TNF gene; Testing; Time; Tube; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Necrosis Factor-alpha; Vascular remodeling; Work; adaptive immunity; base; chemokine; combat; cytokine; cytotrophoblast; fetal; immunocytochemistry; immunoregulation; implantation; improved; in utero; inhibitor/antagonist; macrophage; matrigel; monocyte; mortality; mouse model; neutralizing antibody; novel; pathogen; pregnant; response; sperm cell; trafficking

DESCRIPTION (provided by applicant): Implanting human cytotrophoblasts (CTBs) invade an underlying decidua comprised of decidual cells and such immune cells as macrophages (MFs) and dendritic cells (DCs). These specialized antigen-presenting cells (APCs) mediate innate immunity, subsequent activation of the adaptive immune system and in the development of immune tolerance. Perturbation of the balance between defense against pathogens and tolerance of the semi-allogeneic embryo in the decidua contributes to preeclampsia-toxemia (PET), a leading cause of perinatal and maternal morbidity and mortality. PET is associated with an aberrant maternal immune response that restricts CTB invasion and leads to impaired remodeling of the spiral arteries into large bore low resistance vessels necessary to increase uterine blood flow to the developing feto-placental unit. In support of the hypothesis that an excess influx and activation of MFs and DCs impair CTB invasion and promotes PET, we observed a marked excess of MFs and DCs in preeclamptic decidua. In leukocyte-free first trimester decidual cells, we found that the pro-inflammatory cytokines, tumor necrosis factor-a (TNF-1) and interleukin-1 beta (IL-12), profoundly enhanced expression of macrophage-colony stimulating factor (M-CSF), granulocyte- macrophage-colony stimulating factor (GM-CSF), which activate immature MFs and DCs to mature MFs and DCs as well as an array of monocyte/macrophage- and DC-recruiting chemokines. We also found that the direct inhibition of CTB invasion by macrophages was enhanced by conditioned media from IL-12-treated decidual cell culture. Our central hypothesis is that pro-inflammatory cytokines dysregulate trafficking and activation of APCs by targeting decidual cells and, thus, contribute to the immune modulation and the development of PET. To test this hypothesis, we will 1) identify those chemokines responsible for recruiting APCs using immune cell migration assays; 2) determine whether M-CSF and GM-CSF play roles in activating APCs by examining effector molecules, activation markers and functional assays for antigen-presenting activity; 3) elucidate the effects of TNF-1 - or IL-12 -treated decidual cells on CTB invasion and vascular remodeling using co-culture of CTBs, APCs and endothelial cells; 4) use a novel MF- or DC-depleted PET mouse model to evaluate the effects of activated APCs on the development of PET. This work will lead to better understanding of the pathogenesis of PET and the development of effective prevention and therapies to combat PET. Consequently, stress and financial burden for affected family and society will be significantly reduced. PUBLIC HEALTH RELEVANCE: Preeclampsia is a multi-system disorder that complicates 5% to 10% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality worldwide. This study of the immunological basis of preeclampsia will result in new therapies to combat this complication during pregnancy. Hence, the welfare of affected families and society will be considerably improved.

描述（由申请人提供）：植入人类细胞增多质细胞（CTB）侵犯了由决定的细胞和诸如巨噬细胞（MFS）和树突状细胞（DCS）等免疫细胞组成的潜在decIDUA。这些专门的抗原呈递细胞（APC）介导先天免疫，随后激活适应性免疫系统以及免疫耐受性的发展。防御病原体的平衡与半合成性胚胎在Decidua中的耐受性之间的平衡促进了先兆子痫（PET），这是围产期和孕妇发病率和死亡率的主要原因。 PET与异常的母体免疫反应有关，该反应限制了CTB侵袭，并导致螺旋动脉重塑为大孔中的重塑，以增加子宫血液流动到发育中的Feto-placeNTALTENT单位所需的低抗性血管。为了支持MFS和DC的过量涌入和激活损害CTB侵袭并促进PET的假设，我们观察到先兆子痫前期的MFS和DC明显过量。在不含白细胞的头三个月决结膜细胞中，我们发现促炎性细胞因子，肿瘤坏死因子-A（TNF-1）（TNF-1）和白介素-1β（IL-12），深刻增强了巨噬细胞 - 殖民地 - 殖民地刺激因子（M-CSF），粒状 - 乳腺细胞的表达（MOCTORPHALE-COL）的表达。 MFS和DCS到成熟的MFS和DC，以及一系列单核细胞/巨噬细胞和DC恢复趋化因子。我们还发现，来自IL-12处理的cant培养的条件培养基可以增强巨噬细胞对CTB侵袭的直接抑制作用。我们的中心假设是，促炎性细胞因子通过靶向dec骨细胞，使APC的运输失调和激活，从而有助于免疫调节和PET的发展。为了检验该假设，我们将1）确定使用免疫细胞迁移测定法募集APC的趋化因子； 2）确定M-CSF和GM-CSF是否通过检查效应子分子，激活标记和功能测定抗原活性在激活APC中起角色； 3）使用CTB，APC和内皮细胞共培养TNF-1-或IL-12处理的判决细胞对CTB侵袭和血管重塑的影响； 4）使用新型的MF或DC缺失的PET小鼠模型来评估活化的APC对PET发展的影响。这项工作将使人们更好地理解宠物的发病机理，并开发有效的预防和对抗PET的疗法。因此，受影响家庭和社会的压力和经济负担将大大减轻。公共卫生相关性：子痫前期是一种多系统疾病，使所有怀孕的5％至10％复杂化，并且是孕产妇和胎儿发病率和死亡率的主要原因。这项关于先兆子痫的免疫学基础的研究将导致新疗法在怀孕期间对抗这种并发症。因此，受影响家庭和社会的福利将得到很大的改善。