Blood, 1 July 2002, Vol. 100, No. 1, pp. 1-2
Radiosensitization of recipient stem cells promotes
engraftment
For a long time it has been accepted that
engraftment of stem cells requires formation of "space" in the
recipient marrow. In the past few years, this concept has been
challenged by observations showing that significant donor chimerism can
be obtained in mice without induction of hypoplasia. Even in
nonmyeloablated or unprepared hosts, donor engraftment can be achieved
provided that large numbers of stem cells are transplanted (Stewart et
al, Blood. 1993;81:2283-2289). This has resulted in the dogma of stem
cell competition as a major factor determining stem cell engraftment.
This concept has been applied in allogeneic
nonmyeloablative transplantations in
humans, wherein high numbers of stem cells are transplanted
following a conditioning regimen consisting of short-lasting
intensive immune suppression without myeloablation.
Noach and colleagues (page 312) elegantly demonstrate that growth
factor treatment of recipient mice prior to receiving low-dose irradiation and syngeneic stem cell transplantation results in increased long-term donor engraftment levels. They present evidence that this is related to depletion of remaining recipient stem cells. In
their study they applied 3 different schedules of growth factor
treatment that were administered for 1 or 7 days. One-day growth factor
treatment resulted in reduced radiosensitivity of recipient stem cells,
whereas treatment for 7 days resulted in enhanced radiosensitivity and
a significant decrease in the number of recipient stem cells. After
treatment with growth factors for one week, a marked enhancement of
engraftment was observed. In recipients pretreated for one day with
combinations of growth factors, initial engraftment was decreased in
comparison with controls. These data suggest that short-term growth
factor treatment mediates radioprotection, whereas longer treatment
results in radiosensitization. These observations are reminiscent of
earlier studies with other cytokines (ie, interleukin-1) that mediate protection from lethal radiation (Neta et al, J Immunol.
1986;136:2483-2485). Although most of the data are compatible with the
hypothesis that engraftment levels are determined by stem cell
competition, some of the data are unexplained by this hypothesis. In
animals receiving a short-term treatment with SCF/IL-11 or SCF/FL, an
increase in primitive stem cells (CAFCs, day 35) was observed after TBI
in comparison with controls not receiving growth factor treatment. The
hypothesis predicts decreased levels of engraftment in these recipients, but instead increased levels were observed.
The mechanisms underlying the observed stem cell depletion and
enhancement of engraftment remain unclear from the present study. It
has been suggested that sensitivity to irradiation is dependent on the
cell-cycle status of stem cells, but this has not been addressed. A
direct effect of growth factor treatment on engraftment is also not
excluded. Furthermore, engraftment levels changed in time,
possibly as a result of secondary effects of irradiation on the
recipient marrow stroma.
An important question for the clinical application of this
approach is whether a similar effect occurs in an allogeneic setting. In nonmyeloablative transplantations, where high numbers of
donor stem cells compete with residual host stem cells, depletion of recipient stem cells could help to promote donor chimerism. However, this first requires additional studies addressing the effect of growth
factor treatment on T cells and NK cells that are involved in graft rejection.
Willem E. Fibbe
University of Leiden
