Decreased thymopoietic capacity contributes to the severe and clinically significant immune deficiency seen after bone marrow transplantation (BMT). One mechanism for thymopoietic failure is damage to the interleukin 7 (IL-7)-producing thymic epithelial cells (TECs) by irradiation and chemotherapy, which can be partially treated by IL-7 administration. Pretreatment of BMT recipients with kera-tinocyte growth factor (KGF, or Fgf7), an epithelial cell-specific growth factor, protects mucosal, cutaneous, and pulmonary epithelial cells from cytotoxic therapy-induced damage in experimental murine models. Like other epithelial cells, TECs specifically express KGF receptors. Because KGF specifically protects KGF receptor-bearing epithelial cells and post-BMT immune deficiency is caused by loss of TECs, we hypothesized that KGF pretreatment would improve post-BMT thymic function. To test the hypothesis, BMT recipient mice were given KGF or placebo prior to congenic or allogeneic BMT. Administration of KGF before mu-rine BMT significantly increased the capacity of the thymus to generate donor-derived thymocytes. KGF pretreatment also normalized the proportion of thymic subpopulations, increased the number of naive T cells in the periphery, and improved the response to neoantigen immunization. KGF treatment caused increased production of intrathymic IL-7, and the thymopoietic effects of KGF required an intact IL-7 signaling pathway. These results demonstrate that KGF may have immunomodulatory effects by a unique mechanism of protection of TECs. Furthermore , thymic injury and prolonged posttransplantation immune deficiency in BMT recipients can be prevented by KGF administration. (Blood. 2002;99:4592-4600)

Interleukin-7 (IL-7) is the major thymopoietic cytokine. Injections of IL-7 after murine bone marrow transplantation (BMT) correct defects in thymic differentiation, including thymic hypocellularity, abnormal differentiation of CD3 ؊ CD4 ؊ CD8 ؊ (triple-negative [TN]) thymocytes into CD4 ؉ CD8 ؉ (double-positive [DP]) cells, and antigen-specific mature T-lymphocyte proliferation. To determine whether IL-7 production is decreased in BMT recipients, BMT was performed with congenic murine donor-recipient strains and escalating doses of pre-BMT conditioning. Increasing doses of radiation resulted in decreased thymic cellularity and maturation from the TN to the DP stage. Quantitative reverse transcription-polymerase chain reaction analyses demonstrated that intrathymic production of IL-7 was significantly decreased in irradiated mice than in nonirradiated controls. Decline in IL-7 transcript levels was correlated with the dose of radiation administered. Analyses of the numbers of CD45 ؊ major histocompatibility complex class II ؉ thymic stromal cells suggested that the mechanism for the decreased IL-7 production was loss of IL-7-producing thymic stromal cells. Experiments indicated that pre-BMT conditioning with radiation led to decreased stromal production of IL-7 and consequent blocks in the maturation of thymocytes. They provided a mechanism for both the abnormal thymopoiesis observed after BMT and the previously observed beneficial effects of IL-7 administration in murine models. Impaired production of IL-7 by thymic stroma may be a general model for the clinically observed adverse effects of cytotoxic therapy on thymopoiesis. IntroductionThe immune deficiency observed after bone marrow transplantation (BMT) is a major cause of morbidity and mortality in patients who undergo transplantation and results in prolonged susceptibility to infection. 1,2 Some of the immunologic defects observed after BMT have included abnormalities of thymopoiesis, activation of T lymphocytes, and antibody production. [3][4][5][6] The thymus has been demonstrated to be a target of graft-versus-host disease (GVHD), and GVHD is associated with decreased thymopoietic capacity after BMT, resulting in decreased thymic output. 7,8 However, abnormal numbers of circulating T lymphocytes have been observed in patients without GVHD, suggesting that other mechanisms besides GVHD suppress the production of new T lymphocytes. 5 Thymopoietic defects may be due to the effects of radiation or chemotherapy on the thymic microenvironment. In addition, these effects may be age related. Analyses of patients undergoing either high-dose chemotherapy or BMT have shown an age-related decline in the production of new T lymphocytes. 9-11 Abnormal numbers of T lymphocytes are especially evident in adult recipients of T-cell-depleted, matched, unrelated donor transplants, suggesting that the combined effects of age, alloreactivity, and high-dose cytotoxic therapy result in clinically significant defects in thymopoiesis. 11 We have been studying the thymopoietic ...