We hypothesize that the isolation of thymic epithelial precursor cells, their ex vivo growth and subsequent transfer into recipients exposed to radio-chemotherapy will enhance both the restoration of T cell repertoire complexity and T cell function following allogeneic bone marrow transplantation. Conditioning treatment in the context of lymphohematopoietic stem cell transplantation is important for the successful engraftment of the new lymphohematopoietic system. However, from the time of conditioning until the full development of a functional T cell compartment, the recipient is at risk for the development of potentially life-threatening bacterial, fungal, viral and protozoan infections. The rapid speed of recovery and the generation of a normal complexity of the immune competence are greatly limited by structural alterations to and functional changes of the thymus following the pre-conditioning regimen as this treatment in adversely affects both the composition and function of distinct thymic stromal cells. Since the thymus provides the physiological microenvironment for the development of the majority of T lymphocytes and its function is critical for the successful establishment and maintenance of the immune system's capacity to distinguish between vital self and injurious non-self. Replacement of thymic function in T cell deficient bone marrow recipients using cell transfer of thymic epithelial stem/precursor cells constitutes the overall goal of this Project. The identification of thymic epithelial precursor cells and a better understanding of the signals that control their ex vivo growth and expansion are the focus of a series of experiments designed to lead to a novel therapeutic approach using thymic epithelial cell replacement therapy. Here, we propose a methodical, sequential, and incremental approach to identify and characterize a population of intrathymic epithelial cells that encompass the capacity as a precursor/stem cell to completely form a functional epithelial thymic microenvironment. We have identified such precursor cells in the mouse to express the cell marker MTS24, a distinctive surface glycoprotein. We plan to detail the molecular and cellular characteristics of different thymic MTS24+ cell populations to attract lymphoid precursor cells, to support their maturation and to control their TCR selection. In parallel, we will elucidate the gene expression profile of MTS24+ stem/precursor cells in order to identify phenotypic characteristics that will aid in understanding their function and improve the physical isolation of these cells. We seek to maintain and expand this population of MTS24+ stem/precursor cells in vitro while maintaining their complex functionality. Finally we propose to test whether these thymic epithelial cells will enhance in a murine BMT model the recovery from T cell immunodeficiency secondary to conditioning with chemo-radiotherapy. Taken together, we propose to provide a comprehensive molecular and cellular analysis of MTS24 vcells and plan to assess their use for cell replacement therapy to correct the life-threatening immunodeficiency following bone marrow transplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ET-1 (02))
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Macchiarini, Francesca
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University Hospital Basel
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Irla, Magali; Hollander, Georg; Reith, Walter (2010) Control of central self-tolerance induction by autoreactive CD4+ thymocytes. Trends Immunol 31:71-9
Hauri-Hohl, Mathias M; Keller, Marcel P; Gill, Jason et al. (2007) Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation. Blood 109:4080-8
Hollander, Georg; Gill, Jason; Zuklys, Saulius et al. (2006) Cellular and molecular events during early thymus development. Immunol Rev 209:28-46