Decidual T Cells in Immune-mediated Pregnancy Loss

蜕膜 T 细胞在免疫介导的妊娠丢失中的作用

• 批准号: 8932614
• 负责人: Ram Raj Singh
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932614
• 关键词: Adoptive Transfer; Animals; Antigens; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Autoimmune Diseases; Blood Vessels; Cells; Characteristics; Complication; Data; Decidua; Dendritic Cells; Future; Goals; Health; Human; Immune; Immunization; Individual; Inflammatory; Lead; Leukocytes; Lipids; Lupus; Lymphoid; Lymphoid Tissue; MHC Class I Genes; Mediating; Mucous Membrane; Mus; Myocardial Infarction; Organ; Outcome; Pathogenesis; Patients; Phenotype; Phospholipids; Population; Pregnancy; Pregnancy Outcome; Pregnancy loss; Pregnant Women; Production; Recurrence; Role; Stroke; Systemic Lupus Erythematosus; T-Lymphocyte; Thrombosis; Translating; Uterus; Wild Type Mouse; Woman; Work; antigen binding; base; cytokine; fetal; implantation; in vivo; killer T cell; macrophage; novel; peripheral blood; pregnant; public health relevance

 DESCRIPTION (provided by applicant): The pregnant uterine mucosa, called decidua, contains ~15-30% of leukocytes in early pregnancy in humans. Recent studies have detected natural killer T cells in human and mouse decidua. The murine peri-implantation uterus contains an expanded population of natural killer T cells, but their function in pregnancy remains unclear. Natural killer T cells are known to react with lipid antigens bound to a non-classical MHC class I-like lipid antigen presenting molecule called CD1d. In preliminary work, we have identified T cells that react with phospholipid (PL) antigens in the decidua, and lymphoid organs of mice as well as in peripheral blood of humans. These novel PL-reactive T cells (PL-T) are relatively abundant in the decidua compared to lymphoid organs in mice and secrete cytokines upon immunization with PL antigens in vivo. The PL-T cells are restricted by CD1d. Such PL-T cells are relatively more in the decidua of lupus mice than in healthy strains. The goal of this R21 Exploratory proposal is to understand the role of PL-T cells in immune-mediated pregnancy loss. Guided by our novel observations, we hypothesize that PL-T cells are altered in lupus mice; such altered PL-T cells induce pregnancy loss. In Aim 1, we will determine the role of PL-T cells on pregnancy outcome in mice with lupus and anti-phospholipid syndrome. In Aim 2, we will begin to translate animal findings. Specifically, we will determine if PL-T cells exist in the decidua of humans, and whether peripheral blood and decidual PL-T cells from patients with lupus/anti-phospholipid syndrome display an activated phenotype with increased production of pro-inflammatory cytokines compared to PL-T cells from normal pregnant women. It is hoped that the study will advance our understanding of decidual immune cells in fetal health and elucidate a novel pathogenetic mechanism of immune-mediated pregnancy loss in lupus and autoimmune diseases.

 描述（由适用提供）：孕妇的子宫粘膜称为Decidua，在人类早期怀孕中含有约15-30％的白细胞。最近的研究检测到人和小鼠Decidua中的天然杀伤细胞。鼠植入子宫周围的子宫含有扩大的天然杀伤细胞群体，但其在妊娠中的功能尚不清楚。已知天然杀手T细胞与与非经典MHC I类脂质抗原呈CD1D结合的脂质抗原反应。在初步工作中，我们已经确定了在决策中与磷脂（PL）抗原反应的T细胞，小鼠的淋巴机器人以及人类的周围血液中。这些新型的PL反应T细胞（PL-T）在决定用体内PL抗原免疫后决定在小鼠和秘密细胞因子的决定中相对丰富。 PL-T细胞受CD1D限制。这种PL-T细胞在狼疮小鼠的决策中比在健康菌株中要多。该R21探索性建议的目的是了解PL-T细胞在免疫介导的妊娠丧失中的作用。在我们新颖的观察结果的指导下，我们假设PL-T细胞在狼疮小鼠中发生了改变。这种改变的PL-T细胞会诱导妊娠丧失。在AIM 1中，我们将确定狼疮和抗磷脂综合征小鼠中PL-T细胞对妊娠结局的作用。在AIM 2中，我们将开始翻译动物发现。具体而言，我们将确定是否存在PL-T细胞 与正常孕妇的PL-T-T细胞相比，狼疮/抗磷脂综合征患者的deciDUA是否与狼疮/抗磷脂综合征患者的PL-T细胞相比，是否表现出激活的表型，与正常孕妇的PL-T细胞相比，促炎性细胞因子的产生增加。希望这项研究能够提高我们对胎儿健康中的判决免疫力的理解，并阐明狼疮和自身免疫性疾病中免疫介导的妊娠丧失的新型致病机制。