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Major histocompatibility complex class II-mediated inhibition of
hematopoiesis in long-term marrow cultures involves apoptosis and is
prevented by c-kit ligand [see comments]
DS Hong, C Beckham, R Huss, JW Lee, D Hockenbery, JA Ledbetter and HJ Deeg
Clinical Research Division, Fred Hutchinson Cancer Research Center,
Seattle, WA 98104, USA.
Expression of major histocompatibility complex (MHC) class II molecules is
developmentally regulated and lineage dependent. Their role in
hematopoiesis is not well defined. Previous studies in a canine model
showed that dogs given 920 cGy of total body irradiation, transplanted with
autologous marrow, and treated with anti-MHC class II monoclonal antibody
(MoAb) immediately posttransplant experienced only a transient granulocyte
recovery that was followed by graft failure. In the present study, the
effect of anti-MHC class II MoAbs on canine in vitro hematopoiesis was
investigated. Anti-MHC class II MoAb H81.9 or B1F6 (both recognizing
nonpolymorphic determinants) had no inhibitory effect when added directly
to colony-forming unit-granulocyte-macrophage (CFU- GM) grown in agar.
However, the addition of intact MoAb or as F(ab')2 fragments to long-term
marrow cultures (LTMCs) resulted in a dose- dependent inhibition of the
generation of CFU-GM among nonadherent cells. Inhibition was most profound
with MoAb added at the time of initiation of culture. However, even if MoAb
was added 3 weeks after recharging LTMCs, CFU-GM generation rapidly
decreased. In addition, the number of adherent cells in LTMCs decreased;
predominantly fibroblast- like cells with prominent cytoplasmic
vesiculation remained. Acridine orange/ethidium bromide staining and
TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling
(TUNEL) tests showed an increase in the proportion of apoptotic cells in
both the nonadherent and adherent compartments. Binding of anti-MHC class
II MoAb to unfractionated marrow cells resulted in an increase in free
(Ca2+)i; no changes in tyrosine phosphorylation pattern were observed. The
addition of stem cell factor (SCF), but not granulocyte colony-stimulating
factor or granulocyte-macrophage colony-stimulating factor, to LTMCs
prevented apoptosis, and the generation of CFU-GM was indistinguishable
from controls. Similarly, a supportive adherent layer was maintained. Thus,
anti-MHC class II MoAbs interfere with hematopoiesis both in vitro and in
vivo. The mechanism involves programmed cell death in subpopulations of
adherent and nonadherent cells. Inhibition of hematopoiesis is abrogated by
exogenous SCF.
Volume 86,
Issue 9,
pp. 3341-3352,
11/01/1995
Copyright © 1995 by The American Society of Hematology
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