In vivo synergy between recombinant human stem cell factor and recombinant human granulocyte colony-stimulating factor in baboons enhanced circulation of progenitor cells

Abstract

Recombinant human stem cell factor (rhSCF) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) are synergistic in vitro in stimulating the proliferation of hematopoietic progenitor cells and their precursors. We examined the in vivo synergy of rhSCF with rhG-CSF for stimulating hematopoiesis in vivo in baboons. Administration of low-dose (LD) rhSCF (25 micrograms/kg) alone did not stimulate changes in circulating WBCs. In comparison, administration of LD rhSCF in combination with rhG-CSF at 10 micrograms/kg or 100 micrograms/kg stimulated increases in circulating WBCs of multiple types up to twofold higher than was stimulated by administration of the same dose of rhG-CSF alone. When the dose of rhG-CSF is increased to 250 micrograms/kg, the administration of LD rhSCF does not further increase the circulating WBC counts. Administration of LD rhSCF in combination with rhG-CSF also stimulated increased circulation of hematopoietic progenitors. LD rhSCF alone stimulated less of an increase in circulating progenitors, per milliliter of blood, than did administration of rhG-CSF alone at 100 micrograms/kg. Baboons administered LD rhSCF together with rhG-CSF at 10, 100, or 250 micrograms/kg had 3.5- to 16-fold higher numbers per milliliter of blood of progenitors cells of multiple types, including colony-forming units granulocyte/macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), and colony-forming and burst-forming units-megakaryocyte (CFU- MK and BFU-MK) compared with animals given the same dose of rhG-CSF without rhSCF, regardless of the rhG-CSF dose. The increased circulation of progenitor cells stimulated by the combination of rhSCF plus rhG-CSF was not necessarily directly related to the increase in WBCs, as this effect on peripheral blood progenitors was observed even at an rhG-CSF dose of 250 micrograms/kg, where coadministration of LD rhSCF did not further increase WBC counts. Administration of very-low- dose rhSCF (2.5 micrograms/kg) with rhG-CSF, 10 micrograms/kg, did not stimulate increases in circulating WBCs, but did increase the number of megakaryocyte progenitor cells in blood compared with rhG-CSF alone. LD rhSCF administered alone for 7 days before rhG-CSF did not result in increased levels of circulating WBCs or progenitors compared with rhG- CSF alone. Thus, the synergistic effects of rhSCF with rhG-CSF were both dose- and time-dependent. The doses of rhSCF used in these studies have been tolerated in vivo in humans.(ABSTRACT TRUNCATED AT 400 WORDS).

Paradoxical drop in circulating neutrophil count following granulocyte-colony stimulating factor and stem cell factor administration in rhesus macaques

“…G-CSF was molecularly cloned 20 years ago [1][2][3]. It stimulates the production, release and redistribution of mature neutrophils [4][5][6][7][8], and also plays a role in the regulation of neutrophil behavior [9]. The first clinical trials of G-CSF in humans targeted the treatment of chronic neutropenias (cyclic, congenital, and idiopathic) [10][11][12][13].…”

“…This hematopoietic growth factor has become the standard of care for the treatment of patients with genetic and chemotherapy-related neutropenia [4][5][6]8,14,15], and is regularly used to mobilize hematopoietic stem and progenitor cells into circulation so that they can easily be collected by leukapheresis for transplantation [7,16,17]. SCF has been molecularly cloned [18][19][20] and synergistically augments mobilization when given in combination with G-CSF [7,16,17,21]. The combination of G-CSF and SCF is regularly used in non-human primates (NHPs) to maximize the number of CD34 + hematopoietic stem cells in circulation [22].…”

The use of CD34+ mobilized peripheral blood as a donor cell source does not improve chimerism after in utero hematopoietic stem cell transplantation in non‐human primates

“…They express similar patterns of adhesion molecule expression (VLA‐2, VLA‐3, VLA‐5, LFA‐1, ICAM‐1, and L‐selectin) that are known to influence homing and engraftment [9, 43]. In postnatal transplantation models these mobilized peripheral blood cells also demonstrate more rapid engraftment and reconstitution of the hematopoietic system [1, 6, 18]. Unfortunately, despite these potential advantages the level of chimerism was not appreciably different from a group of animals receiving marrow‐derived donor cells.…”

Improved Amphotropic Retrovirus‐Mediated Gene Transfer into Hematopoietic Stem Cells

“…Previous studies in rhesus monkeys and baboons by ourselves and others have shown maximal CFU-GM mobilization on days 4-6 after initiation of SCF and G-CSF. 39 CD34-enriched peripheral blood stem and progenitor cells were transduced for 96 hours in suspension culture with either LNL6 or G1Na neo vectors (titer: 1-5 × 10 5 ) using a protocol similar to that used in human clinical trials. 2 Fourteen days after discontinuation of the G-CSF/SCF treatment, bone marrow was harvested, enriched for cells expressing CD34, and transduced under identical conditions as the peripheral blood, using whichever vector was NOT used to transduce the peripheral blood cells.…”