Abstract
Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome and in pulmonary fibrosis. However, there is controversy with respect to the impact of plerixafor on neutrophil dynamics in the lung, which may affect its safety profile. In this study, we investigated the kinetics of endogenous neutrophils by direct imaging, using confocal intravital microscopy in mouse bone marrow, spleen, and lungs. Neutrophils are observed increasing their velocity and exiting the bone marrow following plerixafor administration, with a concomitant increase in neutrophil numbers in the blood and spleen, while the marginated pool of neutrophils in the lung microvasculature remained unchanged in terms of numbers and cell velocity. Use of autologous radiolabeled neutrophils and SPECT/CT imaging in healthy volunteers showed that plerixafor did not affect GM-CSF-primed neutrophil entrapment or release in the lungs. Taken together, these data suggest that plerixafor causes neutrophil mobilization from the bone marrow but does not impact on lung marginated neutrophil dynamics and thus is unlikely to compromise respiratory host defense both in humans and mice.
Highlights
The CXCR4 antagonist plerixafor (AMD3100) is used clinically for the acute mobilization of HSPCs for bone marrow transplants.[1]
To directly test whether the blood neutrophilia was due to neutrophil release from the bone marrow (BM), we undertook intravital microscopy (IVM) of the mouse calvarium, identifying BM vasculature by i.v. injection of Cy5-Dextran and endogenous neutrophils by i.v. injection of low dose anti-Ly6G-PE mAb
The use of low dose anti-Ly6G mAb (2–5 μg/mouse), as an imaging tool for neutrophil dynamics, has been widely reported and several studies have shown that it does not compromise neutrophil dynamics such as rolling, adhesion, and intravascular crawling in a number of tissues including the lung.[28,29]
Summary
The CXCR4 antagonist plerixafor (AMD3100) is used clinically for the acute mobilization of HSPCs for bone marrow transplants.[1] Plerixafor causes a dose- and time-dependent blood leukocytosis in humans.[2] Studies in both mice and humans have shown that plerixafor affects neutrophil dynamics, most notably increasing circulating neutrophil numbers as early as an hour after administration.[3,4,5] Initial work from our group showed that when plerixafor was infused directly into the femoral artery of anaesthetized mice, there was an increase in the number of neutrophils collected via cannulation of the femoral vein, suggesting that plerixafor led to the mobilization of neutrophils from the bone marrow (BM).[3] This supported the hypothesis that the CXCR4-CXCL12 axis is important, for HSPC, and neutrophil retention in the bone marrow.[3,6] Consistent with this hypothesis, a severe blood neutropenia is a characteristic of the Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, a genetic disease associated with gain-of-function
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