Improved Human-Mouse Chimera Models for Biodefense

描述（由申请人提供）：将有许多基础和临床相关的研究应用的实验模型，其中毒素，环境污染物和传染性病原体对人体免疫系统的影响可以有效地研究。当这种物质可能具有物种特异性作用时，尤其如此，而且重要的是要记住，人类淋巴细胞在许多方面与小鼠的淋巴细胞不同。用人类造血细胞构建嵌合小鼠的能力为研究开辟了重要的新途径，这些模型的效率稳步提高。人类B淋巴细胞生成的所有正常阶段都在移植小鼠的骨髓中表现出来，最近令人兴奋的报道表明，也可能产生功能性T淋巴细胞和抗原呈递细胞。然而，这些实验系统的承诺目前被一些限制所抵消。这些因素包括人类细胞发生率的巨大动物间差异，以及新形成的B细胞寿命短的事实。我们将通过操纵受体小鼠中可能阻碍人类干细胞植入和扩增的激素和内源性物质来解决这个试点项目中的第一个问题。此外，将研究具有几种免疫缺陷特征组合的小鼠，以找到最有效地支持人类淋巴细胞生成的小鼠。此外，我们将引入人类细胞因子，其应维持人类B淋巴细胞通过其成熟的最后阶段。在有效移植小鼠中测试免疫功能的简单参数后，我们将尝试引发抗原特异性初次免疫应答。最后，作为一个证明的原则，我们将研究的影响，免疫毒素与复杂的模式对人类淋巴细胞的嵌合小鼠的行动。筛选和研究生物恐怖剂是改进的人-小鼠嵌合体模型的明显应用之一。

DESCRIPTION (provided by applicant): There would be many basic and clinically relevant research applications for experimental models where the effects of toxins, environmental pollutants and infectious agents on the human immune system could be effectively studied. This is especially true when the substance is likely to have species-specific actions, and it is important to remember that human lymphocytes differ from those of mice in a number of ways. The ability to construct chimeric mice with human hematopoietic cells has opened important new avenues for investigation, and the efficiency of those models has steadily improved. All normal stages of human B lymphopoiesis are represented in the bone marrow of transplanted mice, and exciting recent reports suggest that it may also be possible to generate functional T lymphocytes and antigen presenting cells. However, the promise of these experimental systems is currently offset by several limitations. These include tremendous animal-to-animal variation in the incidences of human cells, and the fact that newly formed B cells have a short lifespan. We will address the first problem in this pilot project by manipulation of hormones and endogenous substances in recipient mice that may hinder the engraftment and expansion of human stem cells. Also, mice with several combinations of immunodeficiency traits will be studied to find ones that most efficiently support human lymphopoiesis. Furthermore, we will introduce human cytokines that should sustain human B lymphocytes through final stages of their maturation. After testing simple parameters of immunological function in efficiently grafted mice, we will attempt to elicit antigen specific primary immune responses. Finally, and as a proof of principal, we will examine the effects of an immunotoxin with complex mode of action on human lymphocytes in chimeric mice. Screening and investigation of agents of bioterror are among the obvious applications for improved human-mouse chimera models.