Stem Cell Therapies for Primary Immune Deficiency

该计划的总体目标是开发新的干细胞移植和基因治疗方法，为患有严重联合免疫缺陷(SCID)和其他原发免疫缺陷的患者产生完整的免疫系统。干细胞和祖细胞在深度免疫中的操作 SCID缺陷型患者为揭示干细胞植入、淋巴细胞生成和免疫重建的机制提供了独特的生物学和临床环境。该计划的中心假设是，造血移植物的年龄和宿主环境影响SCID患者免疫系统的最终重建。每个项目都将从不同的角度检验这一假设 和互补性视角。项目1的目标是阐明胸腺血管壁龛在骨髓移植(BMT)后骨髓细胞归巢和植入到新生儿胸腺中的调节作用。项目2将提供有关胎儿和成人B细胞发育和体液免疫反应发展的新信息，特别关注B-1B细胞的个体发育。这些信息对于了解骨髓移植和基因治疗后体液免疫的恢复有很高的相关性。项目3的目标是开发更有效和更安全的方法来治疗SCID 患者使用体内ADA基因传递，我们的数据表明，这种方法在新生儿期和早期婴儿期将最成功。该项目汇集了来自加州大学洛杉矶分校、加州大学洛杉矶分校和加州大学戴维斯分校的经验丰富和合作的调查团队。两个科学核心将通过提供细胞和组织分离和分析以及移植和基因治疗的动物模型方面的专门知识来支持这些项目。当这些项目和核心结合在一起时，将为SCID的干细胞疗法的基础和临床研究提供协同和重点，SCID是最致命的初级免疫缺陷形式。 与公共卫生相关：婴幼儿拥有一种独特的生物学，这使他们对旨在恢复免疫系统的干细胞和基因疗法更有反应。了解提供这种发育优势的机制可能会导致改进治疗年龄较大的儿童和成年人的免疫障碍的方法。

The overall goal of this Program is to develop novel stem cell transplantation and gene therapy approaches to produce an intact immune system in patients with Severe Combined Immune Deficiency (SCID) and other Primary Immune Deficiencies. The manipulation of stem and progenitor cells in the profoundly immune deficient patient with SCID provides a unique biological and clinical setting to unravel mechanisms of stem cell engraftment, lymphopoiesis and immune reconstitution. The central hypothesis of the Program is that the age of the hematopoietic graft and the host environment influences the ultimate reconstitution of the immune system in the patient with SCID. Each of the Projects will test this hypothesis from a different and complementary perspective. The goal of Project 1 is to delineate the role of the thymic vascular niche in the regulation of homing and engraftment of bone marrow cells to the neonatal thymus after bone marrow transplantation (BMT). Project 2 will provide new information regarding fetal and adult B cell development and the development of the humoral immune response, with a specific focus on the ontogeny of B-1 B cells. This information will be highly relevant to understanding the restoration of humoral immunity following BMT and gene therapy. The goal of Project 3 is to develop more effective and safer approaches to treat SCID patients using in vivo ADA gene delivery, an approach that our data suggests will be most successful during the neonatal period and early infancy. The Program brings together an experienced and collaborative team of investigators from CHLA, UCLA and UC Davis. Two scientific cores will support the Projects by providing specialized expertise in cell and tissue isolation and analysis and in animal models of transplantation and gene therapy. When brought together, these Projects and Cores will provide synergy and focus for basic and clinical studies in Stem Cell therapies for SCID, the most lethal form of Primary Immune Deficiency. Relevance to Public Health: Young infants possess a unique biology that makes them more responsive to stem cell and gene therapy aimed at restoring the immune system. Understanding the mechanisms that afford this developmental advantage may lead to improved approaches for immune disorders in older children and adults.