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F. R. Seiler, D. Krumwieh, H. Krieter, T. Macvittie, W. Nothdurft, U. B. Brueckner, K. Messmer, Preclinical studies on the efficacy of CSFs in dogs and subhuman primates, The International Journal Of Cell Cloning, Volume 9, Issue S1, 1991, Pages 40–59, https://doi.org/10.1002/stem.5530090708
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Abstract
Hemopoiesis-stimulating activity of various recombinant human colony-stimulating factors (rhCSFs) has been studied in four different preclinical animal models. The CSFs used were erythropoietin (Epo), granulocyte-macrophage (GM) CSF, granulocyte (G) CSF, interleukin (IL) 3, IL-1β, and mast cell growth factor (MGF) or stem cell factor (SCF). Emphasis was placed on effects induced by combination treatment with varied pairs of the factors. Dogs and primates were chosen because of evidence of efficacy from earlier studies with the single recombinant human factors alone.
The animal models chosen were: 1) isovolemic hemodilution to a hematocrit of 10% (or 20%) of dogs, splenectomized at least three months before start of the study. Additionally, the animals had been primed with Epo (or Epo plus IL-3) on three days daily or five days every other day before hemodilution. 2) Total body irradiation (TBI) of dogs (2.4 Gy) followed by daily treatment with IL-1β (d1-7) plus Epo administered daily over three weeks. 3) TBI of rhesus monkeys (4.5 Gy) and daily treatment with IL-3 and GM-CSF over three weeks. 4) Treatment of healthy normal cynomolgus monkeys with various factor combinations over about two or three weeks.
The results can be summarized as follows: 1) Priming with Epo before blood loss (withdrawal) allows a strikingly enhanced recovery of hematocrit and other hematological parameters. Further evaluation of the role of concomitantly applied CSFs (e.g., IL-3, GM-CSF or G-CSF) on the restoration of immune functions would be desirable. 2) Single CSFs and preferentially factor combinations are valuable agents to reduce irradiation injury and to enhance recovery from bone marrow hypoplasia. 3) Treatment of healthy animals with selected CSF combinations results in a stronger hemopoietic stimulation than with single factors alone. Some particular combinations even stimulate platelet production, e.g., IL-3/GM-CSF, GM-CSF/Epo or G-CSF/IL-3. The results obtained indicate that stimulatory responses of hemopoiesis in normal animals cannot always be compared with the effects seen in compromised animals. It is assumed that the preclinical data obtained in compromised animals may perhaps more realistically reflect what is eventually to be expected in future clinical studies.
