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Adherent lymphokine-activated killer cells suppress autologous human normal
bone marrow progenitors
JS Miller, C Verfaillie and P McGlave
Department of Medicine, University of Minnesota Medical School, Minneapolis
55455.
We have generated a homogeneous population of recombinant interleukin-2
(rIL-2)-stimulated effector cells termed adherent lymphokine-activated
killer cells (A-LAK) from peripheral blood mononuclear cells (PBMNC) of 14
normal individuals and tested the effect of A-LAK cells on autologous
hematopoietic bone marrow (BM) progenitor growth. Enrichment of A-LAK from
PBMNC depended on the propensity of A-LAK precursors to adhere to plastic
and proliferate in the presence of rIL-2. The resultant population had the
morphologic appearance of large granular lymphocytes, and the majority of
cells (73% +/- 4%) expressed the CD56+/CD3- phenotype associated with
rIL-2-stimulated natural killer (NK) cells. The A-LAK population had potent
lytic activity in chromium release assays against both NK-sensitive (K562)
and NK-resistant (Raji) targets. When BM mononuclear cells (BMMNC) were
coincubated with autologous A-LAK and rIL-2 (1,000 U/mL) added at the start
of culture, dose-dependent suppression of burst-forming unit-erythroid
(BFU-E) and colony-forming unit mix (CFU-MIX) colony growth was observed at
effector to target ratios (E:T) ranging from 0.25:1 to 5:1 (maximal
suppression BFU-E = 85% +/- 6%; CFU-MIX = 95% +/- 3%). This suppression was
rIL-2 dose-dependent, and no suppression was seen in the absence of rIL-2.
Depletion of BM monocytes and T lymphocytes did not alter A-LAK suppression
of progenitors coincubated with A-LAK cells. Addition of polyclonal
neutralizing antibodies against both interferon-gamma (IFN- gamma) and
tumor necrosis facto alpha (TNF-alpha) to the coincubation culture
completely abrogated the suppressive effect of A-LAK on BFU-E and CFU-MIX
colony growth while each neutralizing antibody used alone had intermediate
effects. In contrast to coincubation studies, 36 hours of preincubation of
A-LAK cells with autologous BM (E:T 2.2:1) and rIL- 2 (1,000 U/mL) followed
by plating of preincubated BM cells in hematopoietic progenitor culture
produced significant suppression of day 14 BFU-E (47% +/- 5%), but spared
the more primitive CFU-MIX (7% +/- 9%), suggesting a divergent effect of
A-LAK cells on hematopoietic progenitors at different stages of
differentiation. Addition of neutralizing antibodies against IFN-gamma and
TNF-alpha in preincubation failed to abrogate the suppressive effect of
A-LAK on BFU- E colony growth, suggesting that this suppression occurs by a
different mechanism than that seen in coincubation studies. Previous
studies have demonstrated that the A-LAK population has cytotoxic and
proliferative advantages over other killer cell populations.(ABSTRACT
TRUNCATED AT 400 WORDS)
Volume 77,
Issue 11,
pp. 2389-2395,
06/01/1991
Copyright © 1991 by The American Society of Hematology
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