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Involvement of Fas-Mediated Apoptosis in the Hematopoietic Progenitor
Cells of Graft-Versus-Host Reaction-Associated Myelosuppression
Takehiko Mori,
Takashi Nishimura,
Yasuo Ikeda,
Tomomitsu Hotta,
Hideo Yagita, and
Kiyoshi Ando
From the Division of Hematology, the Departments of
Internal Medicine and Immunology, Research Center for Genetic
Engineering and Cell Transplantation, Tokai University School of
Medicine, Kanagawa; the Division of Hematology, the Department of
Internal Medicine, Keio University School of Medicine, Tokyo; and the
Department of Immunology, Juntendo University School of Medicine,
Tokyo, Japan.
The influence of graft-versus-host (GVH) reaction on the host
hematopoietic cells clinically manifests itself both as adverse reactions in transfusion-associated GVH disease (GVHD) and as a
therapeutic graft-versus-leukemia (GVL) effect in either donor lymphocytes transfusion (DLT) or allogeneic bone marrow (BM)
transplantation. We examined the effect of GVH reaction on the host
hematopoiesis in the murine parent-into-F1 (P1  F1)
model of GVHD. The systemic transfer of 5 × 107 of
C57BL/6 (B6) splenocytes into (B6xDBA/2)F1 mice (BDF1), which results
in acute GVHD, reduced the peripheral blood cell counts, the number of
BM cells, and colony-forming unit-granulocyte macrophage (CFU-GM), whereas the injection of 108 of
DBA/2 cells into BDF1, which results in chronic GVHD, did not affect
hematopoiesis 2 weeks after the transfer. To clarify the mechanism of
such myelosuppression, we examined the Fas expression in both
hematopoietic progenitor cells as well as whole BM cells. The Fas
expressions in each fraction significantly increased in BDF1 mice 2 weeks after the induction of acute GVHD, whereas no such effects were
observed in the BDF1 mice with chronic GVHD. Furthermore, when such BM
cells were incubated with anti-Fas antibody (Jo2), which induces
apoptosis through Fas, the fraction of apoptotic cells increased and
the number of CFU-GM decreased significantly. The in vivo
administration of neutralizing anti-FasL antibody into BDF1 mice
receiving with B6 spleen cells thus protected the host mice from BM
failure. These results indicate that the functional expression of Fas
on hematopoietic cells plays an essential role in the myelosuppressive
effect of GVHD.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 101-107
© 1998 by The American Society of Hematology.
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