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Interferon-gamma constitutively expressed in the stromal microenvironment
of human marrow cultures mediates potent hematopoietic inhibition
C Selleri, JP Maciejewski, T Sato and NS Young
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD
20892-2116, USA.
Clinical and laboratory studies have suggested involvement of
interferon-gamma (IFN-gamma) in the pathophysiology of aplastic anemia. T
cells from aplastic anemia (AA) patients secrete IFN-gamma in vitro,
activated cytotoxic lymphocytes infiltrate aplastic bone marrow (BM), and
IFN-gamma mRNA, not detected in normal BM, is present in BM from most AA
patients. Many patients respond to immunosuppressive therapy with
antithymocyte globulin and cyclosporine. Using long-term BM cultures
(LTBMC) as a tissue culture model of hematopoiesis, we show that IFN-gamma
is a potent inhibitor in the long-term culture- initiating cell (LTC-IC)
assay, the best in vitro surrogate test for human hematopoietic stem cells,
as well as of the output of committed progenitor cells (colony-forming
unit-granulocyte-macrophage [CFU-GM] and burst-forming unit-erythroid
[BFU-E]). In LTBMC, continuous addition of relatively high IFN-gamma
concentrations (1,000 U/mL weekly or 200 U/mL every 2 days) was required
for inhibition of secondary colony formation, a measure of LTC-IC number
and clonogenicity. To mimick local production of IFN-gamma, human stromal
cells were engineered by retroviral-mediated gene transfer to express a
transduced IFN-gamma gene. IFN-gamma secreted by stromal cells was far more
potent than exogenous IFN-gamma in its effects in the LTC-IC assay. For
purified CD34+ cells culture in the presence of IFN-gamma stroma
dramatically reduced secondary colony numbers as well as production of
CFU-GM and BFU-E. Supernatants from these cultures contained only about 20
U/mL of IFN-gamma; this quantity of cytokine, when added to LTBMC, had
little effect on hematopoiesis. The mechanism of hematopoietic suppression
was related to the inhibition of cell cycle progression and induction of
apoptosis of CD34+ cells. There was no apparent effect of local low-level
IFN-gamma production on stromal cell function, as reflected in cell
morphology, cell surface phenotype, or expression of hematopoietic growth
factor genes. LTBMC with genetically altered stromal cells offers an in
vitro model of immune suppression of hematopoiesis in AA and may be helpful
in testing certain therapeutic modalities. We infer from our data that
local production of low levels of inhibitory cytokine is sufficient to
markedly inhibit hematopoiesis and to destroy stem cells and more mature
progenitor cells.
Volume 87,
Issue 10,
pp. 4149-4157,
05/15/1996
Copyright © 1996 by The American Society of Hematology
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