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

• 批准号: 7780851
• 负责人: Gay M Crooks
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780851
• 关键词: Allogenic; Immune; Thymus Gland; implantation; postnatal; reconstitution

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）：由于胸腺的发育缺陷，在Digeorge Anomaly中发生严重的先天性T淋巴细胞减少症。已经进行了出生后，同种异体培养的胸腺片段的手术植入，以便在这些患者中为胸腺波下的适当微环境提供适当的微环境。尽管采用了这种方法，但周围T细胞数量一直保持较低，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胸腺重构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的小鼠模型中使用人胸膜嵌合体来创建一个平台，我们可以在细胞水平上划定如何在人类胸腺植入物中产生胸腺细胞，以及如何改善胸腺胰岛素。为了实现这一目标，我们将从对正常人类胸腺胰岛和胸腺血管生态位的研究中汇总出信息。使用免疫缺陷的鼠模型，我们注意到新生儿胸腺为造血干细胞移植后的快速胸腺播和胸腺素提供了独特的接受环境。我们的数据表明，新生儿和成人胸腺血管之间存在定性差异，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响应性脉管系统介导了快速而稳健的胸腺蛋白酶。此外，我们提出，植入胸腺组织中VEGF的表达将改善宿主造血细胞的胸腺重构速度和质量。我们提出以下具体目的：1。确定在植入产后培养的胸腺后建立人胸腺胞菌的细胞机制。 2。确定人类产后胸腺植入物中的VEGF表达是否会改善植入物存活率和胸腺波西斯。除了这些研究与Digeorge异常的治疗直接相关性外，这些研究还将提供一种在实验上进行人类胸腺微环境操纵人类胸腺微环境的方法，并在内源性人类血肿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构中的作用可能会提供对胸腺细胞区室内跨言论机理的新颖洞察力。 公共卫生相关性：针对人类胸腺的分子表达的能力具有巨大的治疗潜力，这些潜在的可能性具有巨大的免疫缺陷，例如Digeorge Anomaly以及在整个出生后生活中发展出的胸腺不足状态。