Maternal and fetal immune responses to in utero HSC transplantation

母体和胎儿对宫内 HSC 移植的免疫反应

• 批准号: 7771488
• 负责人: Tippi Mackenzie
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771488
• 关键词: Affect; Allogenic; Allografting; Anatomy; Animal Model; Antigens; B-Lymphocytes; Blood; Cell Transplants; Cells; Chimera organism; Chimerism; Development; Disease; Effector Cell; Engraftment; Environment; Fetus; Foundations; Future; Goals; Graft Rejection; Grant; Hematopoietic; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Human; Immune; Immune response; Immune system; Immunocompetent; Immunologic Deficiency Syndromes; Immunologics; Immunology; Immunosuppression; Injection of therapeutic agent; Intervention; Life; Lymphocyte; Mothers; Organ Transplantation; Outcome; Play; Pregnancy; Process; Research; Research Personnel; Role; Sickle Cell Anemia; Stem cell transplant; T-Lymphocyte; Techniques; Testing; Thalassemia; Time; Training; Transfusion; Transplantation; Work; base; clinical application; congenic; design; fetal; fetal infection; fetus surgery; improved; in utero; in utero transplantation; insight; mouse model; postnatal; pre-clinical therapy; pup; response; stem cell biology; success; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Cellular transplantation into the early gestational fetus is a promising strategy to treat congenital hematopoietic disorders. Theoretically, transplantation of foreign cells into the fetus, prior to the maturation of the immune system, could result in life-long tolerance to the donor. However, most clinical applications have not been successful, indicating there are multiple barriers to the engraftment of transplanted cells. The long-term objective of this research is to understand and overcome these barriers. In the mouse model of in utero hematopoietic stem cell transplantation (IUHSCTx), we and others have shown that the immune response of the host limits engraftment. However, we have recently demonstrated that transplants into normal fetuses carried by immunodeficient mothers are all successful, indicating that the maternal immune system is an important (and previously unrecognized) barrier to IUHSCTx. We have also shown that there is considerable trafficking of immune cells from the mother into the fetus during normal development. We hypothesize that the maternal immune system plays an essential role in limiting the success of IUHSCTx. Therefore, modulating this immune response may help to overcome a significant barrier to engraftment. In Specific Aim 1, we will determine whether maternal B or T cells are necessary for graft rejection. In Aim 2, we will study maternal/fetal cellular trafficking after fetal intervention to determine how maternal cells encounter donor cells to promote rejection. In Aim 3, we will test whether maternal tolerance induction improves engraftment. Understanding the role of the maternal immune system in fetal transplantation has important clinical applications for designing transplantation strategies to treat fetuses with congenital hematopoietic disorders such as sickle cell disease, thalassemias, or immunodeficiencies. Beyond these diseases, tolerance induction to a particular donor can be used for fetuses with anatomic anomalies requiring postnatal organ transplantation. Insights gained into the process of maternal/fetal cellular trafficking may also improve our understanding of maternal/fetal tolerance during normal and abnormal pregnancy. As a training grant, these studies will allow me to develop a strong foundation in immunology so that I can ultimately become an independent investigator studying stem cell transplantation in the fetal environment. My training setting, with experts in immunology and stem cell biology and strong institutional support, is ideal for achieving this goal. Relevance: We believe that transplanting stem cells into the fetus-before the immune system matures-can potentially allow us to treat congenital diseases and avoid toxic immunosuppression. While this strategy has had limited success in humans, we continue to explore various ways to improve our techniques. The aim of this grant is to understand the role of the mother's immune system in rejecting the cells transplanted into the fetus so that we can devise approaches to optimize acceptance.

描述（由申请人提供）：将细胞移植到早期妊娠胎儿中是治疗先天性造血障碍的一种有前途的策略。理论上，在免疫系统成熟之前将外源细胞移植到胎儿体内，可能会导致对供体的终生耐受。然而，大多数临床应用并未成功，这表明移植细胞的植入存在多重障碍。这项研究的长期目标是了解并克服这些障碍。在子宫内造血干细胞移植（IUHSCTx）的小鼠模型中，我们和其他人已经证明宿主的免疫反应限制了移植。然而，我们最近证明，移植到免疫缺陷母亲携带的正常胎儿中都是成功的，这表明母体免疫系统是 IUHSCTx 的重要（且之前未被认识到）障碍。我们还表明，在正常发育过程中，有大量免疫细胞从母亲转移到胎儿中。我们假设母体免疫系统在限制 IUHSCTx 的成功方面发挥着重要作用。因此，调节这种免疫反应可能有助于克服植入的重大障碍。在具体目标 1 中，我们将确定母体 B 细胞或 T 细胞是否是移植物排斥所必需的。在目标 2 中，我们将研究胎儿干预后母体/胎儿细胞的运输，以确定母体细胞如何遇到供体细胞以促进排斥。在目标 3 中，我们将测试母体耐受诱导是否可以改善植入。了解母体免疫系统在胎儿移植中的作用对于设计移植策略来治疗患有先天性造血障碍（例如镰状细胞病、地中海贫血或免疫缺陷）的胎儿具有重要的临床应用。除了这些疾病之外，对特定供体的耐受诱导还可用于患有需要出生后器官移植的解剖异常的胎儿。对母体/胎儿细胞贩运过程的深入了解也可以提高我们对正常和异常妊娠期间母体/胎儿耐受性的理解。作为培训补助金，这些研究将使我在免疫学方面打下坚实的基础，以便我最终能够成为一名研究胎儿环境中干细胞移植的独立研究者。我的培训环境拥有免疫学和干细胞生物学专家以及强大的机构支持，是实现这一目标的理想选择。 相关性：我们相信，在免疫系统成熟之前将干细胞移植到胎儿体内，有可能使我们能够治疗先天性疾病并避免有毒的免疫抑制。虽然这种策略在人类身上取得的成功有限，但我们仍在继续探索各种方法来改进我们的技术。这笔赠款的目的是了解母亲的免疫系统在排斥移植到胎儿的细胞中的作用，以便我们能够设计出优化接受的方法。