Gerjo A. Velders

Biology of IL‐8‐Induced Stem Cell Mobilization

Abstract: The CXC chemokine interleukin‐8 (IL‐8) has profound hematopoietic activities following systemic administration. It induces the rapid mobilization of cells with lymphomyeloid repopulating ability in mice and of hematopoietic progenitor cells in monkeys. In this paper, evidence is presented that stem cell mobilization in mice requires the functional expression on the β2‐integrin leukocyte function‐associated antigen‐1 (LFA‐1). In monkeys, systemic injection of IL‐8 is followed by a significant increase in the circulating levels of the matrix metallo proteinase gelatinase‐B (MMP‐9). Based on these findings, the hypothesis is discussed that mature neutrophils serve as intermediate cells in IL‐8‐induced stem cell mobilization by the release of proteinases.

Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory mediators in cytokine-induced HSC/HPC mobilization, we considered a possible role for protease inhibitors in the induction of HSC/HPC mobilization. Bone marrow (BM) extracellular extracts that were obtained from murine femurs after 0.5 Gy of TBI contained an inhibitor of elastase. Also, after low-dose TBI, both Serpina1 mRNA and protein concentrations were increased in BM extracts, compared with extracts that were obtained from controls. The inhibitory activity in BM extracts of irradiated mice was reversed by addition of an Ab directed against Serpina1. To further study a possible in vivo role of Serpina1 in HSC/HPC mobilization, we administered Serpina1 before IL-8 injection. This administration resulted in an almost complete inhibition of HSC/HPC mobilization, whereas heat-inactivated Serpina1 had no effect. These results indicate that low-dose TBI inhibits cytokine-induced HSC/HPC mobilization and induces Serpina1 in the BM. Because exogenous administration of Serpina1 inhibits mobilization, we propose that radiation-induced Serpina1 is responsible for the inhibition of HSC/HPC mobilization. Also, we hypothesize that cytokine-induced HSC/HPC mobilization is determined by a critical balance between serine proteases and serine protease inhibitors.

Involvement of Proteases in Cytokine‐Induced Hematopoietic Stem Cell Mobilization

Abstract: The number of circulating stem cells and progenitor cells can be increased by physiological stress, such as exercise, stress, and infections. The process of shifting the stem cells from the bone marrow into the peripheral blood is referred to as “mobilization” or “egress.” Cytokine‐mobilized hematopoietic progenitor cells (HPCs) are currently used for autologous or allogeneic stem cell transplantation in a variety of malignant and nonmalignant diseases. In spite of the wide‐spread use of mobilized peripheral blood stem cells for transplantation, the mechanisms underlying mobilization are still incompletely understood. Here we discuss the role of neutrophils and proteases as mediators of stem cell mobilization.

Hematopoietic stem and progenitor cells are differentially mobilized depending on the duration of Flt3-ligand administration

Background Flt3-ligand is a cytokine that induces relatively slow mobilization of hematopoietic cells in animals and humans in vivo. This provides a time-frame to study hematopoietic stem and progenitor cell migration kinetics in detail. Design and Methods Mice were injected with Flt3-ligand (10 μg/day, intraperitoneally) for 3, 5, 7 and 10 days. Mobilization of hematopoietic stem and progenitor cells was studied using colony-forming-unit granulocyte/monocyte and cobblestone-area-forming-cell assays. The radioprotective capacity of mobilized peripheral blood mononuclear cells was studied by transplantation of 1.5×106 Flt3-ligand-mobilized peripheral blood mononuclear cells into lethally irradiated (9.5 Gy) recipients. Results Hematopoietic progenitor cell mobilization was detected from day 3 onwards and prolonged administration of Flt3-ligand produced a steady increase in mobilized progenitor cells. Compared to Flt3-ligand administration for 5 days, the administration of Flt3-ligand for 10 days led to a 5.5-fold increase in cobblestone-area-forming cells at week 4 and a 5.0-fold increase at week 5. Furthermore, transplantation of peripheral blood mononuclear cells mobilized by 5 days of Flt3-ligand administration did not radioprotect lethally irradiated recipients, whereas peripheral blood mononuclear cells mobilized by 10 days of Flt3-Ligand administration did provide 100% radioprotection of the recipients with significant multilineage donor chimerism. Compared to the administration of Flt3-ligand or interleukin-8 alone, co-administration of interleukin-8 and Flt3-ligand led to synergistic enhancement of hematopoietic stem and progenitor cell mobilization on days 3 and 5. Conclusions These results indicate that hematopoietic stem and progenitor cells show different mobilization kinetics in response to Flt3-ligand, resulting in preferential mobilization of hematopoietic progenitor cells at day 5, followed by hematopoietic stem cell mobilization at day 10.

Multi-center randomized open label phase II trial on three rituximab dosing schemes in immune thrombocytopenia patients.

The overall short-term treatment efficacy of rituximab (R) in immune thrombocytopenia (ITP) is reported to be approximately 58%.[1][1],[2][2] With four once-weekly 375 mg/m2 doses, responses of 31% after two years,[2][2] and 21% after five years[2][2] can be expected with a median clinical