The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: Synergism of tumor necrosis factor and interferon-γ

H. E. Broxmeyer, D. E. Williams, L. Lu, S. Cooper, S. L. Anderson, G. S. Beyer, R. Hoffman, B. Y. Rubin

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Abstract

The influences of human tumor necrosis factor (TNF) (LuKII) recombinant human TNF-α natural human interferon-γ (HuIFN-γ), recombinant HuIFN-γ, and natural HuIFN-α were evaluated alone or in combination for their effects in vitro on colony formation by human bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells incubated at 5% CO2 in lowered (5%) O2 tension. TNF (LuKII) and recombinant TNF-α caused a similar dose-dependent inhibition of colony formation from CFU-GM, BFU-E, and CFU-GEMM. Day 7 CFU-GM colonies were more sensitive than both day 14 CFU-GM colonies and day 7 CFU-GM clusters to inhibition by TNF. BFU-E colonies and CFU-GEMM colonies were least sensitive to inhibition with TNF. The suppressive effects of TNF (LuKII) and recombinant TNF-α were inactivated respectively with hetero-anti-human TNF (LuKII) and monoclonal anti-recombinant human TNF-α. The hetero-anti-TNF (LuKII) did not inactivate the suppressive effects of TNF-α and the monoclonal anti-recombinant TNF-α did not inactivate TNF (LuKII). The suppressive effects of TNF did not appear to be mediated via endogenous T lymphocytes and/or monocytes in the bone marrow preparation, and a pulse exposure of marrow cells with TNF for 60 min resulted in maximal or near maximal inhibition when compared with cells left with TNF for the full culture incubation period. A degree of species specificity was noted in that human TNF were more active against human marrow CFU-GM colonies than against mouse marrow CFU-GM colonies. samples of bone marrow from patients with non-remission myeloid leukemia were set up in the CFU-GM assay and formed the characteristic abnormal growth pattern of large numbers of small sized clusters. These cluster-forming cells were more sensitive to inhibition by TNF than were the CFU-GM colonies and clusters grown from the bone marrow of normal donors. The sensitivity of TNF of colony formation by CFU-GM of patients with acute myelogenous leukemia in partial or complete remission was comparable with that of normal donors. When combinations of TNF and HuIFN were evaluated together, it was noted that TNF (LuKII) or recombinant TNF synergized with natural or recombinant HuIFN-γ, but not with HuIFN-α, to suppress colony formation of CFU-GM, BFU-E, and CFU-GEMM from bone marrow of normal donors at concentrations that had no supressive effects when molecules were used alone. The synergistic interactions of TNF and HuIFN were ablated with either anti-TNF or anti-HuIFN-γ. These results may have physiologic, pathologic, and/or clinical relevance.

Original languageEnglish (US)
Pages (from-to)4487-4495
Number of pages9
JournalJournal of Immunology
Volume136
Issue number12
StatePublished - Aug 27 1986

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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