ABSTRACT
Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic levels of other IL-6 family cytokines/receptors and whether such effects differ between donors. We examined how G-CSF administration influenced C-reactive protein (CRP) levels (85 donors) and serum levels of IL-6 family cytokines/receptors (20 donors). G-CSF increased CRP levels especially in elderly donors with high pretherapy levels, but these preharvesting levels did not influence clinical outcomes (nonrelapse mortality, graft versus host disease). The increased IL-6 levels during G-CSF therapy normalized within 24 h after treatment. G-CSF administration did not alter serum levels of other IL-6-familly mediators. Oncostatin M, but not IL-6, showed a significant correlation with CRP levels during G-CSF therapy. Clustering analysis of mediator levels during G-CSF administration identified two donor subsets mainly characterized by high oncostatin M and IL-6 levels, respectively. Finally, G-CSF could increase IL-6 release by in vitro cultured monocytes, fibroblasts, and mesenchymal stem cells. In summary, G-CSF seems to induce an acute phase reaction with increased systemic IL-6 levels in healthy stem cell donors.
Subject(s)
Blood Donors , Fibroblasts/immunology , Granulocyte Colony-Stimulating Factor/pharmacology , Inflammation Mediators/metabolism , Inflammation/immunology , Monocytes/immunology , Peripheral Blood Stem Cells/immunology , Adolescent , Adult , Aged , Cells, Cultured , Cytokines/metabolism , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Hematopoietic Stem Cell Mobilization , Humans , Inflammation/drug therapy , Inflammation/metabolism , Middle Aged , Monocytes/drug effects , Monocytes/metabolism , Peripheral Blood Stem Cells/drug effects , Peripheral Blood Stem Cells/metabolism , Young AdultABSTRACT
BACKGROUND AIMS: Stem cell mobilization and harvesting by peripheral blood leukapheresis in patients with myeloma can alter plasma levels of certain cytokines. In the present study, we investigated the effects of these interventions on a larger group of cytokines. METHODS: Plasma cytokine levels were determined in 15 patients with myeloma who were undergoing peripheral blood stem cell harvesting, and we compared the patients with healthy donors who were undergoing platelet apheresis. RESULTS: Several cytokines showed altered levels in patients with myeloma when examined after chemotherapy plus granulocyte colony-stimulating factor-induced stem cell mobilization. The most striking effect was increased levels of several CCL (CCL2/3/4) and CXCL (CXCL5/8/10/11) chemokines as well as increased thrombopoietin, interleukin 1 receptor antagonist, interleukin-4, granulocyte colony-stimulating factor and hepatocyte growth factor. Stem cell harvesting by apheresis altered the plasma levels of several mediators (CD40 ligand, interleukin 1 receptor antagonist, CCL5 and CXCL5/8/10/11). Apheresis in patients with myeloma had divergent effects on these chemokine levels, although they were all still significantly higher than for healthy individuals. Thrombapheresis in healthy individuals had only minor effects on plasma cytokine levels. Stem cell graft supernatants showed high levels of several cytokines, especially CCL and CXCL chemokines. Analyses of chemokine profiles in pre-apheresis plasma and graft supernatants suggested that such profiling can be used to detect prognostically relevant differences between patients. CONCLUSIONS: Our results demonstrate that patients with myeloma have an altered cytokine network during stem cell mobilization, and the network is further altered during stem cell harvesting by leukapheresis. These treatment- or procedure-induced alterations involve several mediators known to affect myeloma cell proliferation, migration and survival.
Subject(s)
Cytokines/blood , Hematopoietic Stem Cell Mobilization/methods , Multiple Myeloma/therapy , Transplantation, Autologous , Adult , Antigens, CD34/blood , Blood Component Removal , Female , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Interleukin-4/blood , Leukapheresis , Male , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/pathology , Peripheral Blood Stem Cell TransplantationABSTRACT
BACKGROUND AIMS. Pro-angiogenic cytokines can affect myeloma cell proliferation directly and indirectly through stimulation of cancer-associated angiogenesis. METHODS. We investigated how peripheral blood stem cell (PBSC) collection affected plasma angioregulatory cytokine levels in 15 consecutive myeloma patients. RESULTS. Plasma levels of hepatocyte growth factor (HGF) were significantly increased prior to apheresis in patients compared with donors, and a further increase was detected immediately after PBSC apheresis. HGF levels decreased within 24 h, but were still higher than the levels in healthy donors, whose HGF levels were not altered by platelet apheresis. Pre-apheresis levels of other angioregulatory cytokines, angiopoietin-2 and vascular endothelial growth factor (VEGF), were also increased in patients, whereas angiopoietin-1, angiogenin and basic fibroblast growth factor levels did not differ from healthy controls. PBSC harvesting decreased angiopoietin-1 and VEGF levels, increased the microvascular endothelial cell marker endocan levels but did not affect the other mediators. CONCLUSIONS. Our results show that PBSC apheresis alters systemic angioregulatory profiles in myeloma patients. This cytokine modulation is not a general characteristic of all apheresis procedures and was not seen in healthy platelet donors.
