Improved Human-Mouse Chimera Models for Biodefense

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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.