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 ...

Levofloxacin, ofloxacin, and Bay Y 3118 are new fluoroquinolones with variable in vitro bacteriostatic and bactericidal activities against the Mycobacterium avium complex (MAC). The potential therapeutic activities of these agents both alone and combined with ethambutol were evaluated in a human macrophage test system and in the beige mouse animal test system with MAC strain 101. Bay Y 3118 at a human-equivalent dose of 30 mg/kg/day for 4 weeks caused a significant reduction in mortality compared with that in untreated controls (P = 0.02). Bay Y 3118 also caused significant reductions in the number of MAC organisms in the blood, liver tissue, and spleen tissue compared with those in untreated controls. Levofloxacin at a human-equivalent dose of 200 mg/kg/day was associated with a significant reduction in mortality (10 versus 39%); however, treatment with either levofloxacin or ofloxacin (200 mg/kg/day) did not result in significant reductions in the numbers of MAC organisms in blood, liver, and spleen compared with those in untreated controls. When Bay Y 3118 was combined with ethambutol, there was no enhancement in therapeutic activity except in the spleen in terms of CFU per gram (reductions of 89% compared with the untreated control, 63% compared with Bay Y 3118 alone, and 72.5% compared with ethambutol alone). Levofloxacin in combination with ethambutol was more active than either drug alone in the reduction of organisms in blood, liver, and spleen. Bay Y 3118 was the most active fluoroquinolone for monotherapy of MAC infection in beige mice, and the combination of ethambutol plus either levofloxacin or ofloxacin was at least additive. In summary, this study demonstrates that quinolones, although active, are inhibitory against MAC in vivo and that there is little correlation between the activity of quinolones in vitro and the activity in mice.

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