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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-06-1634.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2609-2616
HEMATOPOIESIS
Short-term injection of antiapoptotic cytokine combinations soon
after lethal  -irradiation promotes survival
Francis Hérodin,
Philippe Bourin,
Jean-François Mayol,
Jean-Jacques Lataillade, and
Michel Drouet
From the Centre de Recherches du Service de Santé
des Armées and Centre de Transfusion Sanguine des Armées,
La Tronche and Clamart, France.
Recovery from radiation-induced (RI) myelosuppression depends on
hematopoietic stem and progenitor cell survival and the active proliferation/differentiation process, which requires early cytokine support. Single cytokine or late-acting growth factor therapy has
proved to be inefficient in ensuring reconstitution after severe RI
damage. This work was aimed at evaluating the in vivo survival effect
of combinations of early-acting cytokines whose antiapoptotic
activity has been demonstrated in vitro: stem cell factor (SCF [S]),
FMS-like tyrosine kinase 3 ligand (FLT-3 ligand [F]),
thrombopoietin (TPO [T]), interleukin-3 (IL-3 [3]), and stromal
derived factor-1 (SDF-1). B6D2F1 mice underwent total body irradiation
at 8 Gy cesium Cs 137  radiation (ie, lethal dose 90% at 30 days)
and were treated soon after irradiation, at 2 hours and at 24 hours,
with recombinant murine cytokines, each given intraperitoneally at 50 µg/kg per injection. All treatments induced 30-day survival
rates significantly higher than control (survival rate, 8.3%). 4F
(SFT3) and 5F (4F + SDF-1) were the most efficient combinations
(81.2% and 87.5%, respectively), which was better than 3F (SFT,
50%), TPO alone (58.3%), and SDF-1 alone (29.2%) and also better
than 4F given at 10 µg/kg per injection (4F10, 45.8%) or as a 50 µg/kg single injection at 2 hours (4Fs, 62.5%). Despite delayed
death occurring mainly from day 150 on and possible long-term
hematopoiesis impairment, half the 30-day protective effects of 4F and
5F were preserved at 300 days. Our results show that short- and
long-term survival after irradiation depends on appropriate multiple
cytokine combinations and at optimal concentrations. The proposal is
made that an emergency cytokine regimen could be applied to nuclear
accident victims as part of longer cytokine treatment, cell therapy, or both.
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