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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1586-1597
A Single Dose of Thrombopoietin Shortly After Myelosuppressive Total
Body Irradiation Prevents Pancytopenia in Mice by Promoting Short-Term
Multilineage Spleen-Repopulating Cells at the Transient Expense of
Bone Marrow-Repopulating Cells
Karen J. Neelis,
Trudi P. Visser,
Wati Dimjati,
G. Roger Thomas,
Paul J. Fielder,
Duane Bloedow,
Dan L. Eaton, and
Gerard Wagemaker
From the Institute of Hematology, Erasmus University Rotterdam,
Rotterdam, The Netherlands; and Genentech Inc, South San Francisco, CA.
Thrombopoietin (TPO) has been used in preclinical myelosuppression
models to evaluate the effect on hematopoietic reconstitution. Here we
report the importance of dose and dose scheduling for multilineage
reconstitution after myelosuppressive total body irradiation (TBI) in
mice. After 6 Gy TBI, a dose of 0.3 µg TPO/mouse (12 µg/kg)
intraperitoneally (IP), 0 to 4 hours after TBI, prevented the severe
thrombopenia observed in control mice, and in addition stimulated red
and white blood cell regeneration. Time course studies showed a gradual
decline in efficacy after an optimum within the first hours after TBI,
accompanied by a replacement of the multilineage effects by lineage
dominant thrombopoietic stimulation. Pharmacokinetic data showed that
IP injection resulted in maximum plasma levels 2 hours after
administration. On the basis of the data, we inferred that a
substantial level of TPO was required at a critical time interval after
TBI to induce multilineage stimulation of residual bone marrow cells. A
more precise estimate of the effect of dose and dose timing was
provided by intravenous administration of TPO, which showed an optimum
immediately after TBI and a sharp decline in efficacy between a dose of
0.1 µg/mouse (4 µg/kg; plasma level 60 ng/mL), which was fully
effective, and a dose of 0.03 µg/mouse (1.2 µg/kg; plasma level 20 ng/mL), which was largely ineffective. This is consistent with a
threshold level of TPO required to overcome initial
c-mpl-mediated clearance and to reach sufficient plasma levels
for a maximum hematopoietic response. In mice exposed to fractionated
TBI (3 × 3 Gy, 24 hours apart), IP administration of 0.3 µg TPO 2 hours after each fraction completely prevented the severe thrombopenia
and anemia that occurred in control mice. Using short-term
transplantation assays, ie, colony-forming unit-spleen (CFU-S) day 13 (CFU-S-13) and the more immature cells with marrow repopulating ability
(MRA), it could be shown that TPO promoted CFU-S-13 and transiently
depleted MRA. The initial depletion of MRA in response to TPO was
replenished during long-term reconstitution followed for a period of 3 months. Apart from demonstrating again that MRA cells and CFU-S-13 are separate functional entities, the data thus showed that TPO promotes short-term multilineage repopulating cells at the expense of more immature ancestral cells, thereby preventing pancytopenia. The short
time interval available after TBI to exert these effects shows that TPO
is able to intervene in mechanisms that result in functional depletion
of its multilineage target cells shortly after TBI and emphasizes the
requirement of dose scheduling of TPO in keeping with these mechanisms
to obtain optimal clinical efficacy.
© 1998 by The American Society of Hematology.
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