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dc.contributor.authorColes, Alasdairen
dc.contributor.authorAzzopardi, Lauraen
dc.contributor.authorKousin-Ezewu, Onajiteen
dc.contributor.authorMullay, Harpreeten
dc.contributor.authorThompson, Saraen
dc.contributor.authorJarvis, Lornaen
dc.contributor.authorDavies, Jessicaen
dc.contributor.authorHowlett, Sarahen
dc.contributor.authorRainbow, Danielen
dc.contributor.authorBabar, Judithen
dc.contributor.authorSadler, Timothyen
dc.contributor.authorBrown, Willen
dc.contributor.authorNeedham, Edwarden
dc.contributor.authorMay, Karenen
dc.contributor.authorGeorgieva, Zoyaen
dc.contributor.authorHandel, Adamen
dc.contributor.authorMaio, Stefanoen
dc.contributor.authorDeadman, Maryen
dc.contributor.authorRota, Ioannaen
dc.contributor.authorHollander, Georgen
dc.contributor.authorDawson, Sarahen
dc.contributor.authorJayne, Daviden
dc.contributor.authorSeggewiss-Berhardt, Ruthen
dc.contributor.authorDouek, Danielen
dc.contributor.authorIsaacs, Johnen
dc.contributor.authorJones, Joannaen
dc.date.accessioned2019-05-08T23:30:10Z
dc.date.available2019-05-08T23:30:10Z
dc.date.issued2019-06-20en
dc.identifier.issn2379-3708
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/292553
dc.description.abstractBackground: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates. Methods: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signaljoint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30. Findings: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107 /L vs. 7.733x107 /L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocoldefined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groups Conclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.
dc.description.sponsorshipTrial - MRC and Moulton Trust Funding Me (senior Author) - Wellcome Trust Funding.
dc.publisherAmerican Society for Clinical Investigation
dc.rightsAll rights reserved
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleKeratinocyte growth factor impairs human thymic recovery from lymphopeniaen
dc.typeArticle
prism.issueIdentifier12en
prism.numbere125377en
prism.publicationDate2019en
prism.publicationNameJCI Insighten
prism.volume4en
dc.identifier.doi10.17863/CAM.39714
dcterms.dateAccepted2019-05-02en
rioxxterms.versionofrecord10.1172/jci.insight.125377.en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2019-06-20en
dc.contributor.orcidColes, Alasdair [0000-0003-4738-0760]
dc.contributor.orcidJarvis, Lorna [0000-0002-5760-0125]
dc.contributor.orcidBrown, Will [0000-0002-7737-5834]
dc.contributor.orcidNeedham, Edward [0000-0001-7042-7462]
dc.contributor.orcidGeorgieva, Zoya [0000-0002-9531-8884]
dc.contributor.orcidDawson, Sarah [0000-0001-7401-2192]
dc.contributor.orcidJayne, David [0000-0002-1712-0637]
dc.contributor.orcidJones, Joanna [0000-0003-4974-1371]
dc.identifier.eissn2379-3708
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G1100114)
pubs.funder-project-idWELLCOME TRUST (105924/Z/14/Z)
pubs.funder-project-idWELLCOME TRUST (105924/Z/14/A)
pubs.funder-project-idWellcome Trust (105924/Z/14/Z)
pubs.funder-project-idWellcome Trust (105924/Z/14/A)
pubs.funder-project-idJ P Moulton Charitable Foundation (unknown)
pubs.funder-project-idJ P Moulton Charitable Foundation (unknown)
cam.issuedOnline2019-05-07en
dc.identifier.urlhttps://insight.jci.org/articles/view/125377en


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