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.
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.
Authors: Matias F Martinez; Enzo Alveal; Tomas G Soto; Eva I Bustamante; Fernanda Ávila; Shrikant I Bangdiwala; Ivonne Flores; Claudia Benavides; Ricardo Morales; Nelson M Varela; Luis A Quiñones Journal: Pharmgenomics Pers Med Date: 2020-08-19
Authors: Ellen McKenna; Richard Wubben; Johana M Isaza-Correa; Ashanty M Melo; Aisling Ui Mhaonaigh; Niall Conlon; James S O'Donnell; Clíona Ní Cheallaigh; Tim Hurley; Nigel J Stevenson; Mark A Little; Eleanor J Molloy Journal: Front Immunol Date: 2022-06-01 Impact factor: 8.786
Authors: Pavel Kovalenko; Anne Paccaly; Anita Boyapati; Christine Xu; Gregory St John; Michael C Nivens; John D Davis; Ronda Rippley; A Thomas DiCioccio Journal: CPT Pharmacometrics Syst Pharmacol Date: 2020-06-20
Authors: Nicola Tregay; Malcolm Begg; Anthony Cahn; Neda Farahi; Kathryn Povey; Sujith Madhavan; Rosalind Simmonds; Daniel Gillett; Chandra Solanki; Anna Wong; Joanna Maison; Mark Lennon; Glyn Bradley; Emily Jarvis; Marius de Groot; Fred Wilson; Judith Babar; A Michael Peters; Edith M Hessel; Edwin R Chilvers Journal: Thorax Date: 2019-01-23 Impact factor: 9.139
Authors: Laurence S C Lok; Thomas W Dennison; Krishnaa M Mahbubani; Kourosh Saeb-Parsy; Edwin R Chilvers; Menna R Clatworthy Journal: Proc Natl Acad Sci U S A Date: 2019-09-04 Impact factor: 11.205