Immunomodulatory B7 Family Proteins in the Placenta

胎盘中的免疫调节 B7 家族蛋白

• 批准号: 7159420
• 负责人: MARGARET G PETROFF
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7159420
• 关键词: Allogenic; Allografting; Autoimmune Diseases; B7-DC antigen; Blood; CD28 gene; Cell Culture Techniques; Cell surface; Cells; Cessation of life; Child health care; Cultured Cells; Data; Development; Disruption; Epidermal Growth Factor; Failure; Family; Family member; Fertility; Fetal Growth Retardation; Fetal Viability; Fetus; Genetic; Goals; Health; Histological Techniques; Hormones; Human; Immune response; Immune system; Immunity; Immunologist; In Vitro; Infertility; Infiltration; Interleukin-2; Knowledge; Lead; Leukocytes; Ligands; Light; Long-Term Effects; Lymphocyte; Lymphocyte Activation; Malignant Neoplasms; Maps; Maternal-Fetal Exchange; Mediating; Modeling; Molecular; Mothers; Mus; Pathogenesis; Pathology; Pathway interactions; Patient currently pregnant; Placenta; Planet Mars; Play; Pre-Eclampsia; Pregnancy; Production; Protein Family; Proteins; Range; Regulation; Reproductive History; Research; Research Personnel; Risk; Role; Signal Transduction; Source; Surface; Therapeutic Agents; Tissues; Transplantation; blastocyst; cancer cell; cell type; cellular targeting; cytokine; fetal; implantation; improved; insight; neutralizing antibody; prevent; programs; receptor; reproductive; research study; response; success; trophoblast

DESCRIPTION (provided by applicant): A breakdown in the immunotolerogenic function of the placenta may result in a failure of the placenta to adequately protect the fetus against possible harmful effects of the maternal immune system. This could in turn contribute to certain pathologies of the placenta such as intrauterine growth retardation and preeclampsia, complications that not only put the mother' s health at risk, but also may have long-term effects on the health of the child. Recent studies have unveiled the existence of multiple cell surface-associated proteins belonging to the B7 and CD28 families that are of fundamental importance in immunological tolerance. Our preliminary studies have shown that these molecules are strong candidates for modulation of the maternal immune system by fetal trophoblast cells. In AIM 1 of this proposal, we will map the cellular sources of (a) the B7 family ligands, B7-DC and B7-H2, and (b) their CD28 receptors, PD-1 and ICOS, at the human maternal-fetal interface. Placental tissues and subpopulations of cells of the maternal-fetal interface will be examined for B7 and CD28 family member expression using molecular and histological techniques. In AIM 2, we will elucidate the mechanisms of regulation of BT-H1 and BT-H2 in trophoblast cells. This aim will determine the molecular and cellular mechanisms by which these molecules are regulated. AIM 3 will be to determine the functional effects of B7-H1 and B7-H2 on lymphocyte death, proliferation, and cytokine production. In these studies, human trophoblast cell culture models will be used to dissect the molecular and cellular consequences of signaling from trophoblast B7-H1 and B7-H2 to lymphocytes. Lastly, AIM 4 will evaluate the consequences of disruption of B7-H1 and B7-H2 signaling on cytokine production, leukocyte infiltration, and fetal viability in pregnant mice. In this aim, post-implantation pregnant mice will be treated with neutralizing antibodies and will be evaluated for these reproductive parameters. These studies are expected to yield a wealth of insight on the mechanisms by which successful pregnancy is permitted despite the allogeneic incompatibility between mother and fetus. Further, these studies will advance our knowledge in developing therapies for infertility and a wide range of other ailments such as cancer and autoimmune disease.

描述（由申请方提供）：胎盘免疫耐受功能的破坏可能导致胎盘无法充分保护胎儿免受母体免疫系统可能的有害影响。这反过来又可能导致胎盘的某些病理，如宫内发育迟缓和先兆子痫，这些并发症不仅危及母亲的健康，而且可能对儿童的健康产生长期影响。最近的研究揭示了属于B7和CD 28家族的多种细胞表面相关蛋白的存在，这些蛋白在免疫耐受中具有根本的重要性。我们的初步研究表明，这些分子是胎儿滋养层细胞调节母体免疫系统的强有力的候选者。在本提案的AIM 1中，我们将在人母胎界面绘制（a）B7家族配体B7-DC和B7-H2以及（B）它们的CD 28受体PD-1和ICOS的细胞来源。将使用分子和组织学技术检查胎盘组织和母胎界面细胞亚群的B7和CD 28家族成员表达。在AIM 2中，我们将阐明BT-H1和BT-H2在滋养层细胞中的调节机制。这一目标将确定这些分子被调节的分子和细胞机制。目的3是确定B7-H1和B7-H2对淋巴细胞死亡、增殖和细胞因子产生的功能作用。在这些研究中，人类滋养层细胞培养模型将用于剖析滋养层B7-H1和B7-H2到淋巴细胞的信号传导的分子和细胞后果。最后，AIM 4将评估B7-H1和B7-H2信号传导中断对孕小鼠细胞因子产生、白细胞浸润和胎儿活力的影响。为此，将用中和抗体处理着床后妊娠小鼠，并评价这些生殖参数。这些研究预计将产生丰富的洞察力的机制，成功的怀孕是允许的，尽管同种异体不相容的母亲和胎儿之间。此外，这些研究将推进我们在开发不孕症和广泛的其他疾病（如癌症和自身免疫性疾病）疗法方面的知识。