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Myelosuppressive conditioning is required to achieve engraftment of
pluripotent stem cells contained in moderate doses of syngeneic bone marrow
Y Tomita, DH Sachs and M Sykes
Harvard Medical School, Transplantation Biology Research Center,
Massachusetts General Hospital, Boston 02129.
We have investigated the requirement for whole body irradiation (WBI) to
achieve engraftment of syngeneic pluripotent hematopoietic stem cells
(HSCs). Recipient B6 (H-2b; Ly-5.2) mice received various doses of WBI (0
to 3.0 Gy) and were reconstituted with 1.5 x 10(7) T-cell- depleted (TCD)
bone marrow cells (BMCs) from congenic Ly-5.1 donors. Using anti-Ly-5.1 and
anti-Ly-5.2 monoclonal antibodies and flow cytometry, the origins of
lymphoid and myeloid cells reconstituting the animals were observed over
time. Chimerism was at least initially detectable in all groups. However,
between 1.5 and 3 Gy WBI was the minimum irradiation dose required to
permit induction of long-term (at least 30 weeks), multilineage mixed
chimerism in 100% of recipient mice. In these mice, stable reconstitution
with approximately 70% to 90% donor-type lymphocytes, granulocytes, and
monocytes was observed, suggesting that pluripotent HSC engraftment was
achieved. About 50% of animals conditioned with 1.5 Gy WBI showed evidence
for donor pluripotent HSC engraftment. Although low levels of chimerism
were detected in untreated and 0.5-Gy-irradiated recipients in the early
post-BM transplantation (BMT) period, donor cells disappeared completely by
12 to 20 weeks post-BMT. BM colony assays and adoptive transfers into
secondary lethally irradiated recipients confirmed the absence of donor
progenitors and HSCs, respectively, in the marrow of animals originally
conditioned with only 0.5 Gy WBI. These results suggest that syngeneic
pluripotent HSCs cannot readily engraft unless host HSCs sustain a
significant level of injury, as is induced by 1.5 to 3.0 Gy WBI. We also
attempted to determine the duration of the permissive period for syngeneic
marrow engraftment in animals conditioned with 3 Gy WBI. Stable
multilineage chimerism was uniformly established in 3-Gy-irradiated Ly-5.2
mice only when Ly-5.1 BMC were injected within 7 days of irradiation,
suggesting that repair of damaged host stem cells or loss of factors
stimulating engraftment may prevent syngeneic marrow engraftment after day
7.
Volume 83,
Issue 4,
pp. 939-948,
02/15/1994
Copyright © 1994 by The American Society of Hematology
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