Bone marrow transplant (BMT) is followed by a period of profound and clinically significant immune deficiency. The investigator has shown that interleukin-7 (IL-7) normalized nitrogen and antigen induced proliferation following BMT, and in vivo treatment of mice post-BMT, stimulates T lymphoid engraftment and function. To test the affects of IL-7 in vivo, the investigator established a murine model of BMT followed by subcutaneous administration of IL-7. Using this model in a syngeneic BMT setting, this investigator has demonstrated that this model in a syngeneic BMT setting, the investigator has demonstrated that IL-7 treatment increases the cellularity of the thymus by Day 28 post-BMT to >40X more than control animals; normalizes the thymic by Day 28 post-BMT to .40X more than control animals; normalizes the thymic subpopulations; induces the proliferation of the immature CD3-CD4-CD8-thymocytes; and induces the early (D28) generation of mitogen-responsive T lymphocytes, without the requirement for exogenous cytokine. These results indicate that IL-7 production post-BMT may be a rate-limiting step in T lymphocyte development and suggest that it can be overcome by exogensus IL-7 administration. The hypothesis addressed by the present application is that IL-7 enhances immune reconstitution by inducing the proliferation of an immature population of thymocytes that have not yet undergone thymic selection. The investigator will test. 1) the importance of normal thymic stroma in IL-7-mediated immune reconstitution; 2) the effect of IL-7 on the maturation and diversity of the TCR repertoire post-BMT; 3) the additive or synergistic effects of stem cell factor on IL-7-mediated immune reconstitution; 4) whether IL-7 treatment past-BMT increases the susceptibility to graft-versus-host disease in a minor histocompatibility antigen system; and 5) whether stromal cells engineered with a retroviral vector to express IL-7 can be used to enhance immune reconstitution. The results from these studies will be important for both HS transplantation and gene therapy for immunologic diseases.
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| Chung, Brile; Dudl, Eric; Toyama, Akira et al. (2008) Importance of interleukin-7 in the development of experimental graft-versus-host disease. Biol Blood Marrow Transplant 14:16-27 |
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| Chung, Brile; Dudl, Eric P; Min, Dullei et al. (2007) Prevention of graft-versus-host disease by anti IL-7Ralpha antibody. Blood 110:2803-10 |
| Jahn, Thomas; Leifheit, Erica; Gooch, Stacie et al. (2007) Lipid rafts are required for Kit survival and proliferation signals. Blood 110:1739-47 |
| Min, Dullei; Panoskaltsis-Mortari, Angela; Kuro-O, Makoto et al. (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109:2529-37 |
| Crooks, Gay M; Weinberg, Kenneth; Mackall, Crystal (2006) Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 12:42-6 |
| Baev, Denis V; Peng, Xiao-Hui; Song, Liping et al. (2004) Distinct homeostatic requirements of CD4+ and CD4- subsets of Valpha24-invariant natural killer T cells in humans. Blood 104:4150-6 |
| Chao, Nelson J; Emerson, Stephen G; Weinberg, Kenneth I (2004) Stem cell transplantation (cord blood transplants). Hematology Am Soc Hematol Educ Program :354-71 |
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