Improved Human-Mouse Chimera Models for Biodefense

描述（由申请人提供）：实验模型将有许多基础和临床相关的研究应用，可以有效地研究毒素，环境污染物和感染因子对人体免疫系统的影响。当物质可能具有物种特异性作用时尤其如此，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。构建人类造血细胞嵌合小鼠的能力为研究开辟了重要的新途径，并且这些模型的效率稳步提高。人类B淋巴细胞的所有正常阶段在移植小鼠的骨髓中都有体现，最近令人兴奋的报道表明，它也可能产生功能性T淋巴细胞和抗原提呈细胞。然而，这些实验系统的前景目前被一些限制所抵消。其中包括动物与动物之间在人类细胞发病率上的巨大差异，以及新形成的B细胞寿命较短的事实。在这个试点项目中，我们将通过操纵受体小鼠体内可能阻碍人类干细胞移植和扩增的激素和内源性物质来解决第一个问题。此外，将研究具有多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系统生成的小鼠。此外，我们将引入人类细胞因子，以维持人类B淋巴细胞在其成熟的最后阶段。在测试了有效移植小鼠免疫功能的简单参数后，我们将尝试引发抗原特异性的初级免疫反应。最后，作为原理的证明，我们将研究具有复杂作用模式的免疫毒素对嵌合小鼠人类淋巴细胞的影响。生物恐怖制剂的筛选和调查是改进人类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.