Hematopoiesis Related Effects of SCF in Animals

Some in vivo studies with SCF have been mentioned above, in Subheadings 7.6.1., 7.6.2., 7.7., and 7.9.

In general, preclinical in vivo studies with SCF have been done in mice, rats, dogs, and nonhuman primates with the species-homologous form of recombinant soluble SCF (4,5). Effects seen with respect to hematopoiesis have usually been reversible upon cessation of treatment.

In Sl/Sld mice, long-term administration of SCF brought about dose-related correction of the macrocytic anemia, significant increases in white blood cell and platelet counts, and marked increase in CFU-S in the bone marrow and spleen (4,5,7,50,67). In normal mice and rats administered optimal doses of SCF for 7-21 d, peripheral blood leukocytosis (mostly neutrophilia) was observed; there were tendencies toward ery-throid and lymphoid hypoplasia in the marrow; mast cell hyperplasia was apparent in the marrow, spleen, and other tissues (lung, gastrointestinal tract), but IgE-dependent Ag-induced anaphylactic reactions were surprisingly decreased in SCF-treated vs control animals (Subheading 7.9.) (4,5,99,125,149,150). Observations with respect to stem and progenitor cells in the bone marrow, spleen, and peripheral blood compartments are of particular interest—several studies suggest that administration of SCF affects the proliferation, trafficking, and localization of very primitive hematopoietic cells (e.g., competitive LTR units) and hematopoietic progenitor cells (e.g., CFU-S). Early on, relatively quiescent primitive cells and progenitors appear to be mobilized to the peripheral blood and traffic to the spleen, such that numbers are increased in both of these compartments, and primitive cells and progenitors in the bone marrow are stimulated to cycling and proliferation (116,149-154). Thus a redistribution, with substantial increase in overall numbers, occurs. Subsequently (e.g., by d 14), numbers in the bone marrow may be greatly expanded (155). That proliferative and antiapoptotic effects on primitive cells and progenitors begin early is consistent with observations that SCF administered during the day before 5-FU administration sensitizes mice to hematopoietic suppression/ablation by the 5-FU (156,157).

Rodent studies of the effects of SCF in combination with other cytokines (e.g., G-CSF, GM-CSF) have in some cases been consistent with the synergies seen in vitro. Observations with respect to the marrow, spleen, and peripheral blood upon multiday co-administration of SCF and G-CSF were similar to those with administration of SCF alone except for pronounced synergistic increase in peripheral-blood neutrophils; greater-than-additive increase in peripheral-blood progenitors; and pronounced splenic extramedullary granulopoiesis, erythropoiesis, and megakaryocytopoiesis (4,5,99). SCF also synergistically enhanced IL-2-mediated expansion of functional NK cells in the spleen, bone marrow, and peripheral blood of mice (Subheading 7.7.) (111). Some in vivo synergy with EPO, mostly at the level of erythroid progenitors (BFU-E and CFU-E), has been described (158).

In baboons, optimal doses of SCF given for 28 d caused dose-related increases in bone marrow cellularity and bone marrow hematopoietic progenitors (4,5,7,100). Mul-tilineage increases in white blood cells were pronounced. Hematocrit increased slightly, whereas platelet counts were unchanged. Numbers of peripheral blood hematopoietic progenitors (CFC and CD34+ cells) increased up to 300-fold. Mast cell hyperplasia was apparent in several tissues, including lung, liver, and spleen; was reversible after discontinuation of SCF; and was not associated with obvious histologic or clinical indications of mast cell activation (4,5,121,122).

The synergy observed with SCF in combination with G-CSF in increasing numbers of progenitor cells in the peripheral blood of mice (99) led to systematic preclinical studies, in mice, dogs, and baboons, on the ability of the SCF/G-CSF combination (compared with G-CSF alone) to mobilize PBPCs that will repopulate marrow in transplantation settings (5,7,159,160). The doses of SCF used in these studies were low and produced minimal effects if used alone. When the low-dose SCF was combined with optimal doses of G-CSF, the combinations were synergistic. PBPCs mobilized by SCF plus G-CSF rescued lethally irradiated animals, leading to multilineage, complete, and long-term hematopoietic reconstitution. These studies provided support for human clinical investigations that were done subsequently (160) (see Subheading 8).

The effects of SCF have been studied when it was administered directly in animal models of hematopoietic recovery or reconstitution. In a mouse irradiation model (161), and in a severe combined immunodeficiency-human (SCID-Hu) model (162), SCF was protective when given just before irradiation (i.e., during the preceding 24 h). The protective mechanism appeared to involve, at least in part, SCF-induced cycling and expansion of the hematopoietic progenitor population (5,163). SCF given just before 5-FU was sensitizing to 5-FU rather than protective (156,157); however, when given daily starting 7 d before 5-FU, SCF was protective, probably reflecting the greater expansion of progenitors over the longer period (152,164).

In a mouse model of sublethal irradiation, SCF administered after the irradiation enhanced the recovery of progenitors in the bone marrow and spleen as well as circulating white blood cells and platelets (165). SCF in combination with G-CSF synergis-tically promoted granulocyte recovery when administered after cyclophosphamide treatment (166). In a mouse model of total body irradiation followed by bone marrow transplantation, SCF given after transplantation stimulated hematopoietic recovery, primarily erythroid (167).

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