Differential effects of granulocyte colony-stimulating factor on marrow- and blood-derived hematopoietic and immune cell populations in healthy human donors

Abstract

A recent phase III trial comparing granulocyte colony-stimulating factor (G-CSF)-stimulated bone marrow (G-BM) and G-CSF-mobilized peripheral blood (G-PB) in matched sibling allograft recipients showed that G-BM produced a similar hematologic recovery but a reduced incidence of extensive chronic graft-versus-host disease, indicating differences in the cell populations infused. As a first step toward identifying these differences, we treated a group of healthy adult humans with 4 daily doses of G-CSF 10 microg/kg and monitored the effects on various hematopoietic and immune cell types in the PB and BM over 12 days. G-CSF treatment caused rapid and large but transient increases in the number of circulating CD34+ cells, colony-forming cells, and long-term culture-initiating cells and in the short-term repopulating activity detectable in nonobese diabetic/severe combined immunodeficiency/beta2-microglobulin-null mice. Similar but generally less marked changes occurred in the same cell populations in the BM. G-CSF also caused transient perturbations in some immune cell types in both PB and BM: these included a greater increase in the frequency of naive B cells and CD123+ dendritic cells in the BM. The rapidity of the effects of G-CSF on the early progenitor activity of the BM provides a rationale for the apparent equivalence in rates of hematologic recovery obtained with G-BM and G-PB allotransplants. Accompanying effects on immune cell populations are consistent with a greater ability of G-BM to promote tolerance in allogeneic recipients, and this could contribute to a lower rate of chronic graft-versus-host disease.

Haploidentical, unmanipulated, G-CSF–primed bone marrow transplantation for patients with high-risk hematologic malignancies

“…After G-CSF stimulation, the number of BM CD34 ϩ cells increases 1.4-to 1.7-fold, the number of colony-forming cells 3-fold and the number of long-term culture-initiating cells 50-to 90-fold. 43 Furthermore, G-CSF exerts an intense immunoregulatory effect on BM T cells by down-regulating the expression of adhesion and CD28/B7 molecules and by increasing the absolute number of DC2 APCs favoring a T-cell shift from Th1-to Th2-type cells and inducing an higher production of IL-4 and IL-10 anti-inflammatory cytokines. [44][45][46][47] In transplantations from HLA identical siblings, engraftment of G-CSF-primed BM cells is faster, with an incidence of Ն grade II acute GVHD of only 6.3%.…”

Efficient marking of human cells with rapid but transient repopulating activity in autografted recipients

“…13 Transplantation experiments to examine the properties of individual repopulating cells have further suggested that hematopoietic recovery in mice can be carried out by a very small number of clones when grafts of freshly isolated murine cells are transplanted. [14][15][16][17] In humans, it seems much less likely that the neutrophils and platelets produced immediately after transplantation would represent clonal populations for a number of reasons.…”

Effects of Granulocyte Colony Stimulating Factor on Functional Activities of Endothelial Progenitor Cells in Patients With Chronic Ischemic Heart Disease

“…Thereby, G-CSF activates progenitor cell releasing factors such as neutrophile elastases and matrix-metalloproteinase to release the stem cells from the bone marrow. 13 Within the bone marrow, activated elastases were shown to cleave receptors and integrins. Bone marrow stromal cells express vascular cell adhesion molecule (VCAM)-1/CD 106 that adheres to the integrin ␣4␤1 or very late antigen-4 (VLA-4) expressed by HSCs and EPCs.…”