Effects of tocilizumab on neutrophil function and kinetics
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Authors
Farahi, Neda
Juss, J
Loutsios, C
Solanki, C
Peters, M
Donaldson, F
Porter-Brown, B
Journal Title
European Journal of Clinical Investigation
ISSN
0014-2972
Publisher
Wiley
Language
English
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Lok, L., Farahi, N., Juss, J., Loutsios, C., Solanki, C., Peters, M., Donaldson, F., et al. (2017). Effects of tocilizumab on neutrophil function and kinetics. European Journal of Clinical Investigation https://doi.org/10.1111/eci.12799
Abstract
Background
Decreases in circulating neutrophils (polymorphonuclear leukocytes, PMNs) have been reported in patients treated with the anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and / or bone marrow trafficking without affecting neutrophil function or apoptosis.
Materials and methods
18 healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium-111-labeled neutrophils re-injected, and their kinetics quantified with longitudinal profiling in a whole body gamma-counter. TCZ-treated subjects were divided into two groups according to the extent of reduction in neutrophil count.
Results
Mean day 4 neutrophil counts, as % baseline, were 101.9%, 68.3% and 44.2% in the placebo, TCZ-PMN-’high’ and TCZ-PMN-’low’ groups, respectively (p < 0.001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver / spleen and bone marrow; however, later neutrophil re-distribution to bone marrow was markedly reduced in the TCZ-PMN-low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs 127% TCZ-PMN-low, p < 0.001; day 10, 180% placebo vs 132% TCZ-PMN-low, p < 0.01), with a trend towards higher liver / spleen neutrophil retention.
Conclusions
We have demonstrated for the first time in humans that IL-6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity.
Sponsorship
This work was supported by grants from F Hoffman La Roche
Ltd. and the Evelyn Trust (L.S.C.L.). F.D. and B.P-B. are employees of F Hoffman La Roche Ltd. E.R.C. has received fees from F Hoffman La Roche Ltd.
Funder references
MRC (MR/J00345X/1)
Asthma UK (08/011)
Evelyn Trust (13/41)
Wellcome Trust (197)
WELLCOME TRUST (104384/Z/14/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Identifiers
External DOI: https://doi.org/10.1111/eci.12799
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266765
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