The ability of patients, especially adults, to regenerate T lymphocytes after disease- or treatment-related depletion of the mature T lymphocyte compartment has emerged as a critical problem in clinical medicine. Patients with cancer, primary immune deficiencies, HIV, or recipients of hematopoietic stem cell transplants (HSCT) suffer significant morbidity and mortality because of prolonged immune deficiency. Previous work in our laboratory has demonstrated that T lymphopoiesis after clinical or experimental HSCT recapitulates normal thymic ontogeny. Studies of immunodeficient humans, dogs and/or knockout mice have demonstrated that thymopoiesis depends on the intrathymic production of two stroma-derived cytokines, interleukin-7 (IL-7) and c-kit ligand (KL). IL-7 and KL are synergistically required for the proliferation, survival and differentiation of immature CD3-CD4-CD8- (""""""""triple negative,"""""""" TN) thymocytes, thereby permitting the development of more mature thymocytes. IL-7 and KL are both produced in the thymus by thymic epithelial cells (TEC), which can be isolated by immunophenotype. Once mechanism for the defective thymopoiesis observed after HSCT is the radiation or chemotherapy-induced killing of the TEC which make IL-7 and KL. As a result, progression of thymocyte differentiation from the Tn stage is limited and thymopoiesis is defective. Administration of either recombinant IL-7 after HSCT, or co-transplantation of marrow stromal cells which have been retrovirally transduced with the IL-7 gene results in significantly improved post-HSCT thymopoiesis and immune reconstitution in murine models. The general pathophysiologic model of TEC damage causing thymic insufficiency suggests that regulation of survival or recovery of the TEC after HSCT is critical for post-HSCT thymopoiesis. Keratinocyte growth factor (KGF) is a member of the acidic fibroblastic growth factor family which specifically promotes the proliferation, survival and differentiation of epithelial cells. Administration of KGF before chemotherapy or radiation has been shown to ameliorate the mucosal, cutaneous, and pulmonary toxicity while also decreasing the incidence and severity of graft-versus-host disease (GVHD). Like other epithelial cells, mature TEC express KGF receptors (KGFR) while thymocytes and thymic fibroblasts express KGF. Pre-transplant KGF administration caused sustained normalization of thymopoietic capacity and generation of antigen-specific T lymphocytes. KCF exerted its effects by increasing post-HSCT IL-7 production. The proposed studies in the present grant will test the hypothesis that intrathymic KGF signaling regulates both normal thymopoiesis as well as thymic recovery after radiation and after HSCT. The studies will evaluate the mechanism by which TEC recovery occurs in KGF treated HSCT recipient mice. KGF knockout mice and mice which inducibly express KGF in their thymocytes and T lymphocytes will be used to test the role of thymocyte-derived KGF in normal and post-HSCT thymopoiesis. The studies will provide important information regarding how the thymic microenvironment is maintained and recovered from cytotoxic injury, and how thymocytes influence the development of their microenvironment.
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