GENERATION OF XSCID/HU DOGS

研究人类免疫系统的发育和功能的能力 系统，以及疾病的发病机制和治疗 由于实际和伦理的限制，免疫系统是困难的。 动物模型，如小鼠，只是近似的模型， 此外，对于许多影响人类的疾病， 动物模型存在，因为疾病只影响人。 已经使用了一些策略来尝试研究人类免疫系统， 然而，免疫缺陷小鼠，很明显，小鼠不 提供必要的微环境， 人体免疫系统对XSCID犬的初步研究表明， 犬骨髓和胸腺微环境，不像那些在 小鼠，能够支持成熟的，循环的 当移植人胎儿造血干细胞时人B和T细胞 细胞 本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， 开发犬体内人淋巴细胞生成的体外试验 用于增强和/或加速重构的微环境。的 设计了具体的目标来测试各种移植策略 具有人CD 34+或CD 3 + CD 38-胎肝细胞的XSCID犬， 显示增强供体干细胞在鼠和人骨中的植入 在基因完全不同的个体之间进行骨髓移植这些 包括干细胞的剂量，骨髓（胎儿肝脏）的存在， 衍生的基质细胞和移植前细胞消融。观察指标 将包括人外周血的表型表征 单核细胞，体外人B和T细胞功能， 人免疫球蛋白，以及人初级和次级免疫球蛋白的评价 免疫反应 XSCID-hu狗，由于其大小，它代表了一个理想的实验 小动物模型，其中可重复采集血液样品， 为了研究人淋巴细胞生成的动力学， 免疫系统对传染病病原体的抵抗力，以及测试疫苗和其他 治疗药物在同一动物体内的作用。XSCID-hu狗会 也是一个有价值的实验模型，用于测试 人类基因疗法

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.