GENERATION OF XSCID/HU DOGS

研究人类免疫系统发育和功能的能力 系统，以及疾病的发病机制和治疗 由于实践和道德上的限制，免疫系统是困难的。 动物模型，如老鼠，只是近似的模型，可能不 与人类相关。此外，对于许多影响人类的疾病，没有 动物模型之所以存在，是因为疾病只影响人类。五花八门 已经有一些策略被用来尝试研究人类免疫系统 然而，免疫缺陷的小鼠显然不是这样 提供必要的微环境，为提供稳定、有效的 人类的免疫系统。对XSCID犬的初步研究表明， 犬骨髓和胸腺微环境，不同于 老鼠，是能够支持发育成熟、循环的 人胎儿造血干细胞移植后的人B细胞和T细胞 细胞。 本提案的总体目标是记录XSCID的实用程序 狗作为研究人类淋巴细胞生成和免疫功能的模型，以及 人淋巴细胞在犬体内体外检测方法的建立 促进和/或加速重建的微环境。这个 设计了特定的目标来测试各种移植策略 XSCID犬与人CD34+或CD3+CD38-胎肝细胞已经 显示可增强供体干细胞在鼠骨和人骨中的植入 在基因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(胎肝)的存在 来源的基质细胞，以及移植前的细胞消融。结果衡量标准 将包括人类外周血的表型特征 单个核细胞，在体外人类B和T细胞功能，产生 人免疫球蛋白与人原发性和继发性免疫球蛋白的关系 免疫反应。 XSCID-HU犬，由于它的体型，它代表了一种理想的实验 可重复采集血液样本的小动物模型 为了研究人淋巴细胞生成的动力学，人的免疫反应 免疫系统对传染病病原体，并测试疫苗和其他 随着时间的推移，治疗药物在同一动物中的作用。XSCID-HU狗将会 也是测试策略的有价值的实验模型 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.