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dc.contributor.authorLok, Laurenceen
dc.contributor.authorFarahi, Nedaen
dc.contributor.authorJuss, Jen
dc.contributor.authorLoutsios, Cen
dc.contributor.authorSolanki, Cen
dc.contributor.authorPeters, Men
dc.contributor.authorDonaldson, Fen
dc.contributor.authorPorter-Brown, Ben
dc.contributor.authorChilvers, Edwinen
dc.date.accessioned2017-08-23T13:24:58Z
dc.date.available2017-08-23T13:24:58Z
dc.identifier.issn0014-2972
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266765
dc.description.abstractBackground 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.
dc.description.sponsorshipThis 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.
dc.language.isoenen
dc.publisherWiley
dc.titleEffects of tocilizumab on neutrophil function and kineticsen
dc.typeArticle
prism.publicationNameEuropean Journal of Clinical Investigationen
dc.identifier.doi10.17863/CAM.12428
dcterms.dateAccepted2017-08-06en
rioxxterms.versionofrecord10.1111/eci.12799en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-08-06en
dc.contributor.orcidLok, Laurence [0000-0002-9364-4213]
dc.contributor.orcidChilvers, Edwin [0000-0002-4230-9677]
dc.identifier.eissn1365-2362
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/J00345X/1)
pubs.funder-project-idAsthma UK (08/011)
pubs.funder-project-idEvelyn Trust (13/41)
pubs.funder-project-idWellcome Trust (197)
pubs.funder-project-idWELLCOME TRUST (104384/Z/14/Z)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
cam.issuedOnline2017-08-10en
rioxxterms.freetoread.startdate2018-08-10


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