Preclinical analysis of cytokine therapy in the SCID-hu mouse.
A severe combined immunodeficient (SCID)-hu mouse model implanted with human fetal bone was used to assess the effects of various recombinant human (rh) hematopoietic growth factors, administered either alone or in combination, on human hematopoiesis in vivo. Treatment with rh granulocyte colony-stimulating factor (G-CSF) elicited the expansion of mature neutrophilic granulocyte populations in human marrow. Administration of rh interleukin-3 (IL-3) induced significant increases of eosinophilic granulocyte and burst-forming unit, erythrocyte (BFU-E) activity. The rhIL-6 did not cause significant changes in the subpopulations of human hematopoietic cells within the grafts, but did increase the number of colony-forming unit, granulocyte-macrophage and BFU-E. Pretreatment with rhIL-3 followed by rh erythropoietin (Epo) administration enhanced Epo-induced human erythropoiesis significantly. No synergistic effects on myelopoiesis were observed using sequential treatment with rhIL-3 followed by rhG-CSF. Instead, these factors seemed to work independently, with rhG-CSF increasing the percentage of neutrophils and rhIL-3 increasing the percentage of eosinophils. When administered simultaneously with rhEpo, rhIL-6 showed dose-dependent inhibitory effects on in vivo Epo-induced human erythropoiesis. The rhIL-6 also caused a reduction in the percentage of human neutrophils induced by rhG-CSF. These results suggest that the SCID-hu mouse provides a useful small animal model to assess the in vivo effects of hematopoietic growth factors on human hematopoiesis.
Kyoizumi
S
S
SyStemix Inc., Palo Alto, CA 94303.
Murray
L J
LJ
Namikawa
R
R
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D016025:Bone Transplantation; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D005333:Fetus; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016256:Lewis X Antigen; D051379:Mice; D016513:Mice, SCID; D011247:Pregnancy; D011994:Recombinant Proteins / Q000494:pharmacology
D015703:Antigens, CD; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D015850:Interleukin-6; D016256:Lewis X Antigen; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor