Short-term injection of antiapoptotic cytokine combinations soon after lethal γ-irradiation promotes survival

Abstract

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 g/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 g/kg per injection (4F10, 45.8%) or as a 50 g/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. (Blood. 2003;

Combined pharmacological therapy of the acute radiation disease using a cyclooxygenase-2 inhibitor and an adenosine A3 receptor agonist

“…This holds true also for the combined administration of IB-MECA + meloxicam. Such an early approach to the treatment of irradiated humans would be in agreement with the findings and concepts of Hérodin et al [31][32][33] which emphasize the necessity of "The Sooner The Better" post-irradiation therapy of radiation victims with the aim to influence postirradiation phenomena like cell apoptosis.…”

Mesenchymal stem cells rescue CD34+ cells from radiation-induced apoptosis and sustain hematopoietic reconstitution after coculture and cografting in lethally irradiated baboons: is autologous stem cell therapy in nuclear accident settings hype or reality?

“…39 In fact, as we recently reported, emergency cytokine treatment using 4F offers the opportunity to rescue victims irradiated at high doses. 40,41 The present study suggests that ACT could rather represent a complementary approach to cytokine treatment than a single therapy. Nevertheless, new autologous cell drugs, mainly involving multipotent stem cells, could represent useful tools to treat RI nonhematopoietic toxicity.…”

A Neurovascular Niche for Neurogenesis after Stroke

“…Animals were killed 3, 5, and 7 d after stroke (n ϭ 3, each time point), and their brains were frozen and processed for the presence of biotin-labeled protein using Alexa488-conjugated streptavidin (Invitrogen). For gainand loss-of-function experiments, osmotic minipumps were filled with low and high doses of recombinant Ang1 (0.05 g/100 l and 0.5 g/100 l), receptor-blocking anti-mouse Tie2 antibody (1 g/100 l and 10 g/100 l), recombinant SDF1␤ (0.27 g/100 l and 2.7 g/100 l), and the CXCR4 receptor antagonist AMD3100 (1.5 mg/100 l and 5 mg/100 l; gift from Dr. Edward Hoover, Colorado State University, Fort Collins, CO), based on published results (Witzenbichler et al, 1998;Herodin et al, 2003;Roviezzo et al, 2005). Control stroke and sham animals received vehicle (0.1 M NaPBS, pH 7.4).…”