While the development of increasingly potent chemotherapeutic agents have proven helpful in ridding the body of various malignancies, such regimens demand supportive therapies involving hematologic reconstitutition. One particularly confounding aspect of these treatments has been the reconstitution of a functionally competent immune system, particularly in regards to the T cell limb of the immune system. The thymus is the major site of T cell development. The goal of this project is to characterize the cells and agents in the thymus that are involved in inducing the maturation of T cells and selecting the T cell repertoire. A better understanding of these cells and interactions should aid in the development of more effective reconstitution protocols. To this end we have employed RAG-deficient mice and SCID mice whose lymphocytes are blocked at an early, immature stage of development . To explore the cells that promote T cell development, we have attempted to induce the maturation of these early T cells with defined populations of mature T cells or stem cells from normal or transgenic mice. To investigate the role of specific populations in thymocyte development, we will use flow cytometry to examine their maturational status after having matured in the presence and absence of exogenous TCR+ cells or other inducer cells. Further, because the ability of TCR+ cells to induce thymocyte development may be via an indirect effect on the thymic epithelium, we will use immunohistologic methods to evaluate maturation of thymic epithelium in reconstituted mice. Finally, we plan to investigate the cytokines that may be involved in the induction process. While some of these studies will be performed in vivo, we will also study induction of T cell maturation in a culture system that involves whole fetal thymi exposed to defined populations of T cells or cytokines in vitro. Results from these studies should help elucidate the cells and signalling molecules that are important for T cell development and should aid in the development and testing of strategies targeted to the reconstitution of the human immune system in patients undergoing myeloablative therapies. 1. Shores, E.W., et al. 1994. International Immunology 6:1394 2. van Ewijk, W., E.W. Shores, et al. 1994. Immunology Today15:214.
