Enhancing immune reconstitution after implantation of postnatal allogeneic thymus

出生后同种异体胸腺植入后增强免疫重建

基本信息

批准号：
7532808
负责人：
Gay M Crooks
金额：
$ 6.55万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-19 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7532808
关键词：
Adult Affect Allogenic Architecture Autoimmune Diseases Biology Blood Vessels Bone Marrow Cell Count Cell Survival Cells Chimera organism Clinical Clinical Protocols Data Data Reporting Defect Development DiGeorge Syndrome Engineering Engraftment Environment Event Fourth Pharyngeal Pouch Generations Goals Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Human Immune Implant Infant Life Lymphopenia Maintenance Marrow Mediating Modeling Mus Muscle Neonatal Operative Surgical Procedures Patients Pattern Peripheral Population Process Production Public Health Role Series Speed Staging T-Lymphocyte Tetracycline Tetracyclines Therapeutic Thigh structure Thymic Tissue Thymic epithelial cell Thymus Gland Transplant Recipients Vascular Endothelial Growth Factors fetal implantation improved insight malformation mouse model neonate novel postnatal postnatal human progenitor reconstitution success thymocyte

项目摘要

DESCRIPTION (provided by applicant): Severe congenital T lymphopenia occurs in DiGeorge anomaly as a result of a developmental defect of the thymus gland. Surgical implantation of postnatal, allogeneic, cultured thymic fragments has been performed in an attempt to provide an appropriate microenvironment for thymopoiesis in these patients. Despite some success with this approach, peripheral T cell numbers have remained consistently low and autoimmune disease is a frequent problem. Detailed analysis of the cellular mechanisms of thymic reconstitution that occur within the implants is not possible in the clinical setting. Our goal in this proposal is to use a human marrow- thymus chimera in an immune deficient mouse model to create a platform from which we can delineate on a cellular level how thymocytes are generated in the human thymic implants, and how thymopoiesis might be improved. To achieve this goal, we will bring together information from our studies of normal human thymopoiesis, and of the thymic vascular niche. Using immune deficient murine models, we have noted that the neonatal thymus provides a uniquely receptive environment for rapid thymic seeding and thymopoiesis after hematopoietic stem cell transplantation. Our data shows that qualitative differences exist between the neonate and adult thymic vasculature, and that these differences are mediated by high levels of Vascular Endothelial Growth Factor (VEGF). We hypothesize that the VEGF responsive vasculature of the neonatal thymus mediates rapid and robust thymopoiesis. Furthermore, we propose that expression of VEGF in implanted thymic tissue will improve the speed and quality of thymic reconstitution from host hematopoietic cells. We propose the following Specific Aims: 1. To determine the cellular mechanisms by which reconstitution of human thymopoiesis is established after implantation of postnatal cultured thymus. 2. To determine if VEGF expression in human postnatal thymic implants will improve implant survival and thymopoiesis. In addition to the direct relevance of these studies to the treatment of DiGeorge anomaly, these studies will provide a technically feasible approach to manipulate the human thymic microenvironment experimentally ex vivo, and examine the biology of such manipulations in the context of endogenous human hematopoiesis. Understanding the role of the vascular niche in thymic reconstitution may provide novel insight into mechanisms of cross-talk within the cellular compartments of the thymus. PUBLIC HEALTH RELEVANCE: The ability to target expression of molecules specifically to the human thymus has broad therapeutic potential for both primary immune deficiencies like DiGeorge anomaly and for acquired states of thymic insufficiency that develop throughout postnatal life.

描述（由申请人提供）：由于胸腺发育缺陷，DiGeorge 异常发生严重先天性 T 淋巴细胞减少症。已经进行了出生后同种异体培养胸腺碎片的手术植入，试图为这些患者的胸腺生成提供适当的微环境。尽管这种方法取得了一些成功，但外周 T 细胞数量仍然较低，并且自身免疫性疾病是一个常见问题。在临床环境中不可能对植入物内发生的胸腺重建的细胞机制进行详细分析。我们在该提案中的目标是在免疫缺陷小鼠模型中使用人类骨髓胸腺嵌合体来创建一个平台，通过该平台我们可以在细胞水平上描述人类胸腺植入物中胸腺细胞是如何产生的，以及如何改善胸腺生成。为了实现这一目标，我们将汇集正常人类胸腺生成和胸腺血管生态位的研究信息。使用免疫缺陷小鼠模型，我们注意到新生胸腺为造血干细胞移植后的快速胸腺播种和胸腺生成提供了独特的接受环境。我们的数据表明，新生儿和成人胸腺脉管系统之间存在质的差异，并且这些差异是由高水平的血管内皮生长因子（VEGF）介导的。我们假设新生儿胸腺的 VEGF 反应性脉管系统介导快速而强大的胸腺生成。此外，我们提出，植入的胸腺组织中 VEGF 的表达将提高宿主造血细胞胸腺重建的速度和质量。我们提出以下具体目标： 1. 确定植入出生后培养胸腺后重建人类胸腺生成的细胞机制。 2. 确定人类出生后胸腺植入物中 VEGF 的表达是否会改善植入物的存活和胸腺生成。除了这些研究与迪乔治异常的治疗直接相关之外，这些研究还将提供一种技术上可行的方法来通过离体实验操作人类胸腺微环境，并在内源性人类造血的背景下检查此类操作的生物学。了解血管生态位在胸腺重建中的作用可能为胸腺细胞区室内串扰机制提供新的见解。公共健康相关性：将分子特异性靶向人类胸腺表达的能力对于迪乔治异常等原发性免疫缺陷和在出生后生活中形成的获得性胸腺功能不全状态具有广泛的治疗潜力。