In vivo administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, interleukin-1 (IL-1), and IL-4, alone and in combination, after allogeneic murine hematopoietic stem cell transplantation

Abstract

BALB/c mice (H-2d) given 10 Gy total body irradiation (TBI) followed by 107 bone marrow (BM) and 106 spleen cells from C57BL/6 (H-2b) donor mice received recombinant cytokines intraperitoneally (IP) twice daily. The effect on neutrophil recovery rate, graft-v-host disease (GVHD), and survival was assessed. Four reagents were used: granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-1 (IL-1) and IL-4, both alone and in combination. The most effective combination for increasing the circulating absolute neutrophil account (ANC) above the control value at day 7 posttransplant was the combination of G-CSF and IL-1 (mean AIMC 2.4 ± 1.6 × 109/L as compared with control value of 0.07 ± 0.05, P < .02), followed by G-CSF alone (mean ANC 1.1 ± 0.2, P < .0001), the combination of GM-CSF plus IL-1 (mean ANC 0.8 ± 0.3, P < .002), and the combination of G-CSF plus GM-CSF (mean ANC 0.8 ± 0.3, p < .005). At day 10 posttransplant, the most effective combination in raising the ANC was the combination of G-CSF plus GM-CSF (mean ANC 7.5 ± 2.3 as compared with control value of 3.5 ± 1.1, P < .01), followed by G-CSF alone (mean ANC 6.9 ± 2.1, P < .02). At the doses used, neither G-CSF nor GM-CSF had a deleterious effect on the incidence or severity of GVHD; indeed, GM-CSF was associated with improved survival. In contrast, IL-1 at doses ≥ 100 ng twice daily caused marked early mortality, and there was a suggestion that IL-4 at doses of 500 ng twice daily resulted in increased late mortality, possibly owing to exacerbation of GVHD. This model appears to be of value for exploring the use of hematopoietic growth factors before they are used clinically in marrow allograft recipients. © 1991 by The American Society of Hematology.