Bone marrow transplantation is playing and increasingly important role in the treatment of individuals with hematologic, genetic and immunologic disorders. However, recovery of autologous hemopoiesis often occurs. Partial repopulation of autologous cells (hemopoietic chimeras) has several potential detrimental consequences including potential repopulation with the malignant clone and/or with radiation damaged autologous stem cells, possibly resulting in future leukemias. Additionally, repopulation with autologous cells reduces the potential for an anti-leukemic effect since the host immune system may already be tolerized to malignant cell antigens. The biological basis for transient donor engraftment and the establishment of long-term stable chimeric hemopoietic systems is not well understood, so development of strategies to minimize recovery of autologous hemopoiesis is difficult. Differential proliferation and differentiation of donor and surviving autologous cells may contribute to chimeric hemopoiesis. If so, transplantation of mature cell populations or administration of cytokines that affect cell proliferation and maturation may also affect the extent of donor engraftment. We propose to combine our expertise in hemopoietic stem cell purification and sensitive detection strategies (fluorescence hybridization and in vitro DNA amplification) to 1) measure the dynamics of donor and autologous hemopoietic repopulation at early stages following transplantation and 2) to investigate the basis for preferential repopulation by donor or autologous stem cells in the presence of phenotypically-mature donor cells and cytokines. Specifically, we will: 1) optimize the transgenic mouse model system and associated detection strategies to allow quantitation of donor cells present at low frequency, 2) determine whether autologous cells in radiation-conditioned recipients show a proliferative advantage over transplanted donor cells, 3) determine whether the rate of donor and autologous cell engraftment in the erythroid, lymphoid, and myeloid lineages are regulated independently, and 4) determine whether phenotypically-mature T cells and GM-CSF preferentially promote donor cell proliferation and differentiation. Data generated in this project will contribute to an increased understanding of the factors/conditions influencing the proliferation and differentiation of donor and autologous stem cells in vivo and will facilitate design of strategies to modulate the engraftment process.
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