Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation.
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.
Chung
B
B
Department of Pediatrics, Division of Research Immunology and Bone Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California School of Medicine, 90027, USA.
Barbara-Burnham
L
L
Barsky
L
L
Weinberg
K
K
D000818:Animals; D020296:Animals, Congenic; D016026:Bone Marrow Transplantation; D002452:Cell Count; D002454:Cell Differentiation / Q000528:radiation effects; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000528:radiation effects*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000528:radiation effects; D013601:T-Lymphocytes / Q000473:pathology*; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D019172:Transplantation Conditioning / Q000009:adverse effects*; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D000949:Histocompatibility Antigens Class II; D015851:Interleukin-7