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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4071-4078
RAPID COMMUNICATION
Granulocyte Colony-Stimulating Factor-Mobilized Allogeneic Stem Cell
Transplantation Maintains Graft-Versus-Leukemia Effects Through a
Perforin-Dependent Pathway While Preventing Graft-Versus-Host Disease
Luying Pan,
Takanori Teshima,
Geoffrey R. Hill,
David Bungard,
Yani S. Brinson,
Vijay S. Reddy,
Kenneth R. Cooke, and
James L.M. Ferrara
From the Department of Pediatric Oncology, Dana Farber Cancer
Institute, Boston, MA; and the Departments of Internal Medicine and
Pediatrics, University of Michigan Medical School, Ann Arbor, MI.
Minimization of graft-versus-host disease (GVHD) with preservation
of the graft-versus-leukemia (GVL) effect is a crucial step to improve
the overall survival of allogeneic bone marrow transplantation (BMT)
for patients with hematological malignancies. We and other
investigators have shown that granulocyte colony-stimulating factor
(G-CSF)-mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this
study, we investigated whether G-CSF-mobilized PBSC maintain their GVL
effect in a murine allogeneic transplant model (B6  B6D2F1).
B6 mice (H-2b) were injected subcutaneously with human
G-CSF (100 µg/kg/d) for 6 days and their splenocytes were harvested
on day 7 as a source of PBSC. G-CSF mobilization dramatically improved
transplant survival compared with nonmobilized controls (95% v
0%, P < .001). Systemic levels of lipopolysaccharide and
tumor necrosis factor- were markedly reduced in recipients of
allogeneic G-CSF-mobilized donors, but cytolytic T lymphocyte
(CTL) activity against host tumor target cells p815 was
retained in those recipients. When leukemia was induced in recipients
by coinjection of p815 tumor cells (H-2d) at the time of
transplantation, all surviving recipients of G-CSF-mobilized B6 donors
were leukemia-free at day 70 after transplant, whereas all mice who
received T-cell-depleted (TCD) splenocytes from G-CSF-mobilized B6
donors died of leukemia. When splenocytes from G-CSF-mobilized
perforin-deficient (pfp /) mice were used for
transplantation, 90% of recipients died of leukemia, demonstrating
that perforin is a crucial pathway mediating GVL effects after
G-CSF-mobilized PBSCT. These data illustrate that G-CSF-mobilized
allogeneic PBSCT separate GVL from GVHD by preserving
perforin-dependent donor CTL activity while reducing systemic inflammation.
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