A randomized trial comparing the combination of granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor versus granulocyte colony-stimulating factor for mobilization of dendritic cell subsets in hematopoietic progenitor cell products (original) (raw)
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Biology of Blood and Marrow Transplantation, 2013
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both mobilize CD34 þ stem cells into the blood when administered before apheresis but have distinct effects on dendritic cell (DC) differentiation. We previously demonstrated that the combination of GMþG-CSF results in fewer plasmacytoid DCs (pDCs) when used to mobilize peripheral blood stem cells for autologous transplantation. To test the hypothesis that the content of pDCs in an allograft can be modulated with the cytokines used for mobilization, we randomized the human leukocyte antigenematched sibling donors of 50 patients with hematological malignancies to a mobilization regimen of either GMþG-CSF (n ¼ 25) or G-CSF alone (n ¼ 25). Primary and secondary endpoints included the cellular constituents of the mobilized grafts, the kinetics of posttransplantation immune reconstitution, and clinical outcomes of the transplantation recipients. Grafts from donors receiving GMþG-CSF contained equivalent numbers of CD34 þ cells with fewer pDCs and T cells, with a higher fraction of Th1-polarized donor T cells than G-CSF mobilized grafts. Immune recovery was enhanced among recipients of GMþG-CSF. Survival was not significantly different between transplantation recipients in the two arms. The use of GMþG-CSF modulates immune function and recovery after allogeneic transplantation and should be explored in larger studies powered to evaluate clinical outcomes.
British Journal of Haematology, 1996
Haemopoietic growth factors (HGFs) have been shown to accelerate recovery from severe neutropenia after autologous bone marrow transplantation (ABMT) but their effect on immune reconstitution is not well defined. The present study compares, through randomized trial, the in vivo effect of GM-CSF and G-CSF administration on the immune recovery of patients who underwent ABMT. For that purpose, we have sequentially analysed 14 different T, B and NK lymphoid cell subsets using appropriate dual staining during the first year following transplant (days
Experimental Hematology, 2005
Despite more than 10 years experience using growth factors after allogeneic stem cell transplantation (ASCT), their state in this has not been elucidated. Most studies show that they accelerate myeloid recovery, regardless of whether they are instituted on day 0 or day 10 after transplant. However, this does not correlate with an improvement in the outcome. One disadvantage is that granulocyte colony-stimulating factor (G-CSF) prophylaxis is associated with slower platelet engraftment due to an increase in platelet aggregation. There is also no agreement as regards the value of G-CSF given as prophylaxis after ASCT, the effects on graft-vs-host disease (GVHD), and the survival rate. A large retrospective study from Europe showed that patients with acute leukemia who received bone marrow from HLA-identical siblings and were treated with G-CSF ran a higher risk of acute and chronic GVHD and transplant-related mortality, while the survival and the leukemia-free survival rates were reduced. In contrast, a meta-analysis of 18 small studies showed no evidence of an increase in acute and chronic GVHD, using G-CSF as prophylaxis after ASCT. Two studies from the Center for International Blood and Marrow Transplant Research showed contradictory data. When G-CSF is given to the recipient as prophylaxis, the levels of soluble interleukin-2 receptor-a increase, which aggravates GVHD. When it is given to the donor, G-CSF polarizes T cells to produce T-helper cell-2 cytokines, which reduce GVHD after transplantation. G-CSF has no effect on relapse. Available findings suggest that there is no indication to use G-CSF as prophylaxis after ASCT.
Biology of Blood and Marrow Transplantation, 2004
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 g/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/ 2-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.
Transplantation, 2000
Allogeneic peripheral blood stem cell transplantation (PBSCT) is increasingly used instead of bone marrow transplantation, particularly in HLA identical sibling pairs. Despite the presence of significantly increased numbers of T cells in the PBSC graft, acute graft-versus-host disease (GVHD) is not increased. We have investigated whether granulocyte-colony stimulating factor (G-CSF) administration to PBSCT recipients, both with and without donor G-CSF pretreatment, further modulates acute GVHD in a murine model of PBSCT. Recipients of G-CSF mobilized splenocytes showed a significantly improved survival (P<0.001) and a reduction in GVHD score and serum LPS levels compared with control recipients. G-CSF treatment of donors, rather than recipients, had the most significant effect on reducing levels of tumor necrosis factor (TNF␣) 7 days after transplantation. As a potential mechanism of the reduction in TNF␣, we
Bone Marrow Transplantation, 2002
It has been suggested that the immunological properties of cytokine primed PBSC may reflect the presence of altered levels of cellular components. In this study the changes induced in blood dendritic cell (DC) subsets following G-CSF mobilisation are analysed. Analysis of normal donors (n = 64) demonstrated considerable individual variation in the absolute numbers (؋10 6 /l) of resting blood CD11c ؊ DC (1.2-26.2) and CD11c + DC (0.9-34.7) as well as in the CD11c ؊ /CD11c + DC ratio (0.29-4.13). G-CSF therapy increased CD11c ؊ DC numbers to above the normal range in all normal donors analysed (n = 6) and the CD11c ؊ /CD11c + ratio was also increased to Ͼ2.0 in all donors. Patients undergoing autologous PBSCT showed a heterogeneous response to mobilisation and although total DC and CD11c ؊ DC numbers were increased in the majority (8/14), they remained within the normal range post mobilisation. The CD11c ؊ /CD11c + ratio decreased in 5/15 patients and only three patients had ratios Ͼ2.0 post mobilisation. Post G-CSF the DC from all normal donors and 13/14 patients had an immature phenotype. These results demonstrate that G-CSF mobilisation induces relatively consistent changes in the number and ratio of DC subsets in normal donors, but considerable variation is seen in the response of patients undergoing mobilisation for autologous PBSCT.
Frontiers in Immunology, 2018
Background: Allogeneic hematopoietic stem cell transplantation is associated with a high risk of immune-mediated post-transplant complications. Graft depletion of immunocompetent cell subsets is regarded as a possible strategy to reduce this risk without reducing antileukemic immune reactivity. study design and methods: We investigated the effect of hematopoietic stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) on peripheral blood and stem cell graft levels of various T, B, and NK cell subsets in healthy donors. The results from flow cytometric cell quantification were examined by bioinformatics analyses. results: The G-CSF-induced mobilization of lymphocytes was a non-random process with preferential mobilization of naïve CD4 + and CD8 + T cells together with T cell receptor αβ + T cells, naïve T regulatory cells, type 1 T regulatory cells, mature and memory B cells, and cytokine-producing NK cells. Analysis of circulating lymphoid cell capacity to release various cytokines (IFNγ, IL10, TGFβ, IL4, IL9, IL17, and IL22) showed preferential mobilization of IL10 releasing CD4 + T cells and CD3 − 19 − cells. During G-CSF treatment, the healthy donors formed two subsets with generally strong and weaker mobilization of immunocompetent cells, respectively; hence the donors differed in their G-CSF responsiveness with regard to mobilization of immunocompetent cells. The different responsiveness was not reflected in the graft levels of various immunocompetent cell subsets. Furthermore, differences in donor G-CSF responsiveness were associated with time until platelet engraftment. Finally, strong G-CSF-induced mobilization of various T cell subsets seemed to increase the risk of recipient acute graft versus host disease, and this was independent of the graft T cell levels. conclusion: Healthy donors differ in their G-CSF responsiveness and preferential mobilization of immunocompetent cells. This difference seems to influence post-transplant recipient outcomes.
Biology of Blood and Marrow Transplantation, 2016
The use of granulocyte colony-stimulating factor (G-CSF) primed bone marrow (G-BM) has been recently considered as an alternative to mobilized hematopoietic stem cells from peripheral blood (G-PB), especially in the haploidentical transplant setting. The purpose of this study was to compare the effect of in vivo G-CSF priming on BM and PB hematopoietic, mesenchymal (MSC), and immune cells. Forty healthy donors undergoing BM harvest for haploidentical transplant were given subcutaneous recombinant human G-CSF for 7 days. BM and PB samples were harvested on days −7 and 0. The hematopoietic stem/progenitor cells increased significantly after G-CSF priming in both BM and PB with a selective rise of BM CD34 + CD38 − cell subset. A striking enhancement of the mesenchymal progenitors was detected in G-BM. CD3 + , CD4 + , CD8 + , and CD19 + cell fractions; the naive CD4 + and CD8 + subpopulations; and natural killer and regulatory T cells increased in G-BM, whereas only slight changes were detected in PB. Myeloid dendritic cells (DC1) were significantly upregulated in both G-BM and G-PB, whereas DC2 increased only in G-BM. In conclusion, our results show substantial differences in the biologic effects exerted by G-CSF at BM and PB levels on hematopoietic cells and immune cell fractions. Furthermore, the impressive rise of MSC progenitors in G-BM might also be relevant to provide MSCs for several clinical use.