GENERATION OF XSCID/HU DOGS

XSCID/HU 狗的一代

• 批准号: 6576604
• 负责人: Peter J Felsburg
• 金额: $ 28.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2003-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576604
• 关键词: B lymphocyte; CD antigens; CD3 molecule; CD34 molecule; T lymphocyte; disease /disorder model; dogs; embryo /fetus cell /tissue; flow cytometry; human tissue; immunity; immunocytochemistry; liver cells; lymphopoiesis; polymerase chain reaction; severe combined immunodeficiency; xenotransplantation

The ability to study the development and function of the human immune system, as well as the pathogenesis and treatment of diseases of the immune system is difficult due to practical and ethical limitations. Animal models, such as the mouse, are only approximate models that may not be relevant to man. In addition, for many diseases affecting man, no animals models exist since the diseases only affect man. Various strategies have been used to attempt to study the human immune system in immunodeficient mice, however, it is evident that the mouse does not provide the necessary microenvironment for providing a stable, functional human immune system. Preliminary studies in XSCID dogs suggest that the canine bone marrow and thymic microenvironments, unlike those in the mouse, are capable of supporting the development of mature, circulating human B and T cells when transplanted with human fetal hematopoietic stem cells. The over-all goal of this proposal is to document the utility of the XSCID dog as a model for studying human lymphopoiesis and immune function, and to develop in vitro assays of human lymphopoiesis in a canine microenvironment for enhancing and/or accelerating the reconstitution. The specific aims are designed to test various strategies of transplanting XSCID dogs with human CD34+ or CD3+CD38- fetal liver cells that have been shown to enhance engraftment of donor stem cells in murine and human bone marrow transplants between genetically disparate individuals. These include the dose of stem cells, the presence of bone marrow (fetal liver) derived stromal cells, and pre-transplant cytoablation. Outcome measures will include phenotypic characterization of human peripheral blood mononuclear cells, in vitro human B and T cell function, production of human immunoglobulin, and evaluation of a human primary and secondary immune response. The XSCID-hu dog, due to its size, it represents an ideal experimental small animal model in which repeated blood samples can be collected in order to study the kinetics of human lymphopoiesis, response of the human immune system to infectious disease agents, and to test vaccine and other therapeutic agents in the same animal over time. The XSCID-hu dog would also be a valuable experimental model in which to test strategies for human gene therapy.

研究人体免疫发育和功能的能力 系统，以及疾病的发病机制和治疗 由于实践和伦理的限制，免疫系统是很困难的。 动物模型，例如小鼠，只是近似模型，可能无法 与人相关。此外，对于许多影响人类的疾病，没有 动物模型的存在是因为这些疾病只影响人类。各种各样的 策略已被用来尝试研究人类免疫系统 然而，对于免疫缺陷小鼠来说，很明显，小鼠并没有 提供必要的微环境，以提供稳定、功能性的 人体免疫系统。对 XSCID 狗的初步研究表明 犬的骨髓和胸腺微环境与人类不同 小鼠，能够支持成熟、循环的发育 人类胎儿造血干细胞移植后的人类 B 细胞和 T 细胞 细胞。 该提案的总体目标是记录 XSCID 的实用性 狗作为研究人类淋巴细胞生成和免疫功能的模型，以及 开发犬科动物淋巴细胞生成的体外测定 用于增强和/或加速重建的微环境。这 设计特定目标来测试各种移植策略 带有人类 CD34+ 或 CD3+CD38- 胎儿肝细胞的 XSCID 狗 显示可增强供体干细胞在小鼠和人类骨骼中的植入 基因不同的个体之间的骨髓移植。这些 包括干细胞的剂量、骨髓（胎儿肝脏）的存在 衍生基质细胞和移植前细胞消融。结果衡量 将包括人类外周血的表型特征 单核细胞，体外人 B 和 T 细胞功能，生产 人类免疫球蛋白，以及人类初级和次级的评估 免疫反应。 XSCID-hu 狗由于其体型较大，代表了理想的实验动物 小动物模型，可重复采集血液样本 为了研究人类淋巴细胞生成的动力学、人类的反应 免疫系统针对传染病病原体，并测试疫苗和其他 随着时间的推移，治疗剂在同一动物中的​​作用。 XSCID-hu 狗会 也是一个有价值的实验模型，可以用来测试策略 人类基因疗法。