Effects of tocilizumab on neutrophil function and kinetics
Laurence S C Lok1, Neda Farahi1, Jatinder K Juss1
1Department of Medicine, University of Cambridge, Cambridge, UK.
Background:
Decreases in circulating neutrophils (polymorphonuclear leucocytes, 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:
Eighteen 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-labelled 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.
Insights
Tocilizumab (TCZ) treatment reduces circulating neutrophils by hindering bone marrow trafficking, not by affecting neutrophil function or apoptosis. This study clarifies the mechanism behind TCZ-induced neutropenia in humans.
Area of Science:
- Immunology
- Pharmacology
- Hematology
Background:
- Decreased circulating neutrophils (polymorphonuclear leucocytes, PMNs) are observed in patients receiving anti-interleukin-6 receptor (IL-6R) antibody tocilizumab (TCZ).
- The underlying mechanism for TCZ-induced neutropenia remains unclear.
- This study hypothesizes that TCZ impacts neutrophil margination and/or bone marrow trafficking without altering neutrophil function or apoptosis.
Purpose of the Study:
- To investigate the mechanism of neutropenia associated with tocilizumab (TCZ) treatment.
- To determine if TCZ affects neutrophil function, apoptosis, or trafficking.
- To elucidate the impact of IL-6R blockade on neutrophil kinetics in humans.
Main Methods:
- Eighteen healthy subjects received a single intravenous dose of TCZ (n=12) or placebo (n=6).
- Autologous indium-111-labelled neutrophils were re-injected on day 4, and kinetics were monitored using a whole-body gamma counter.
- TCZ-treated subjects were stratified into 'high' and 'low' neutrophil count reduction groups.
Main Results:
- Neutrophil counts were significantly reduced in TCZ-treated groups (44.2% and 68.3% of baseline) compared to placebo (101.9%).
- Neutrophil function, activation, and apoptosis ex vivo remained unaffected by TCZ.
- In vivo, TCZ markedly reduced neutrophil redistribution to the bone marrow, with a trend towards increased liver/spleen retention, particularly in the TCZ-PMN-low group.
Conclusions:
- Interleukin-6 receptor (IL-6R) blockade with tocilizumab (TCZ) affects neutrophil trafficking to the bone marrow.
- This study provides the first human evidence that TCZ-induced neutropenia is due to altered neutrophil kinetics, not impaired neutrophil function.
- The findings clarify a key mechanism of TCZ's hematological effects.
