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Original Contributions |

Natalizumab and Impedance of the Homing of CD34+ Hematopoietic Progenitors

Christian Saure, MD; Clemens Warnke, MD; Fabian Zohren, MD; Thomas Schroeder, MD; Ingmar Bruns, MD; Ron P. Cadeddu; Christian Weigelt, MD; Ute Fischer, MD; Guido Kobbe, MD; Hans-Peter Hartung, MD; Ortwin Adams, MD; Bernd C. Kieseier, MD; Rainer Haas, MD
Arch Neurol. 2011;68(11):1428-1431. doi:10.1001/archneurol.2011.238.
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Background Treatment with natalizumab, an antibody blocking the α4-integrin, is associated with increased numbers of circulating CD34+ cells in the peripheral blood of patients with multiple sclerosis.

Objective To determine whether natalizumab mobilizes CD34+ cells from or inhibits homing to the bone marrow (BM).

Design Fifty-two patients with relapsing-remitting multiple sclerosis treated with natalizumab were included. Flow cytometric analyses; polymerase chain reaction assays for JC (John Cunningham) virus DNA detection; and adhesion, migration, and apoptosis assays of immunomagnetically enriched peripheral blood and BM CD34+ cells were conducted. A comparison was made with CD34+ cells from granulocyte colony-stimulating factor–mobilized peripheral blood or steady-state BM of age- and sex-matched healthy donors.

Results We found adhesion and migration of peripheral blood–derived CD34+ cells to be reduced. In BM aspirates from natalizumab-treated patients, the cellularity, the proportion, and the adhesive capacity of CD34+ cells were normal. The JC virus was undetectable.

Conclusions Natalizumab mediates an increase in circulating CD34+ cells by interfering with homing to the BM. Thus, CD34+ cells appear unlikely to represent a source mobilizing JC virus out of the BM in patients treated with natalizumab.

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Figures

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Figure 1. Expression of CD49d, CD184, and CD133 on CD34+ cells. A, Representative fluorescence-activated cell-sorting dot plots showing the expression of CD49d on CD34+ cells from the peripheral blood (PB) and bone marrow (BM) of patients with multiple sclerosis treated with natalizumab (NAT). For comparison, dot plots of granulocyte colony-stimulating factor (G-CSF)–mobilized CD34+ cells and BM-derived CD34+ cells of healthy control (HC) patients are shown. B, Percentage of CD34+ cells expressing CD49d, CD184, and CD133 as measured by fluorescence-activated cell sorting. Gray and black bars on the left side represent G-CSF–mobilized CD34+ cells from 5 HCs and PB-derived CD34+ cells from 17 patients with multiple sclerosis receiving NAT therapy. Gray and black bars on the right side represent BM-derived CD34+ cells from 7 HCs and from 9 patients with multiple sclerosis treated with NAT. Error bars indicate mean (SEM). FITC indicates fluorescein isothiocyanate; PE, phycoerythrin.

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Figure 2. In vitro adhesion and migration assays. On the left side is shown the adhesion of CD34+ cells from peripheral blood (PB) (granulocyte colony-stimulating factor [G-CSF], n = 9; natalizumab [NAT], n = 8) and bone marrow (BM) (healthy control [HC] patients, n = 6; NAT, n = 9) to fibronectin. On the right side is shown the migration of CD34+ cells from PB (G-CSF, n = 15; NAT, n = 5) and BM (HC, n = 7; NAT, n = 8) along a stromal-derived factor 1 gradient. Gray bars represent G-CSF–mobilized CD34+ cells and BM-derived CD34+ cells of HCs. Black bars represent CD34+ cells of patients with multiple sclerosis treated with NAT. Error bars indicate mean (SEM).

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Figure 3. Bone marrow smears. Microscopic images of bone marrow smears from 3 healthy donors (A through C) and 3 patients with multiple sclerosis treated with natalizumab (D through F).

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