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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1601-1606
TRANSPLANTATION
Radiosensitivity of thymic interleukin-7 production and
thymopoiesis after bone marrow transplantation
Brile Chung,
Lucia Barbara-Burnham,
Lora Barsky, and
Kenneth Weinberg
From the Department of Pediatrics, Division of Research
Immunology and Bone Marrow Transplantation, Children's Hospital Los
Angeles, University of Southern California School of Medicine.
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.
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