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In Vitro and In Vivo Evidence That Ex Vivo Cytokine Priming of Donor
Marrow Cells May Ameliorate Posttransplant Thrombocytopenia
Mariusz Z. Ratajczak,
Janina Ratajczak,
Boguslaw Machalinski,
Rosemarie Mick, and
Alan M. Gewirtz
From the Departments of Pathology and Laboratory Medicine,
Biostatistics and Epidemiology, and Internal Medicine, University of
Pennsylvania School of Medicine, Philadelphia, PA.
Thrombocytopenia is typically observed in patients undergoing
hematopoietic stem cell transplantation. We hypothesized that delayed
platelet count recovery might be ameliorated by increasing the number
of megakaryocyte colony- forming units (CFU-Meg) in the hematopoietic
cell graft. To test this hypothesis, we evaluated cytokine combinations
and culture medium potentially useful for expanding CFU-Meg in vitro.
We then examined the ability of expanded cells to accelerate platelet
recovery in an animal transplant model. Depending on the cytokine
combination used, we found that culturing marrow CD34+
cells for 7 to 10 days in serum-free cultures was able to expand CFU-Meg ~40 to 80 times over input number. Shorter incubation periods
were also found to be effective and when CD34+ cells were
exposed to thrombopoietin (TPO), kit ligand (KL), interleukin-1
(IL-1), and IL-3 in serum-free cultures for as few as 48 hours, the
number of assayable CFU-Meg was still increased ~threefold over input
number. Of interest, cytokine primed marrow cells were also found to
form colonies in vitro more quickly than unprimed cells. The potential
clinical utility of this short-term expansion strategy was subsequently
tested in an in vivo animal model. Lethally irradiated Balb-C mice were
transplanted with previously frozen syngeneic marrow mononuclear cells
(106/mouse), one tenth of which (105) had been
primed with [TPO, KL, IL-1a, and IL-3] under serum-free conditions
for 36 hours before cryopreservation. Mice receiving the primed frozen
marrow cells recovered their platelet and neutrophil counts 3 to 5 days
earlier than mice transplanted with unprimed cells. Mice which received
marrow cells that had been primed after thawing but before
transplantation had similar recovery kinetics. We conclude that
pretransplant priming of hematopoietic cells leads to faster recovery
of all hematopoietic lineages. Equally important, donor cell priming
before transplant may represent a highly cost-effective alternative to
constant administration of cytokines during the posttransplant recovery
period.
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 353-359
© 1998 by The American Society of Hematology.
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