Keratinocyte growth factor impairs human thymic recovery from lymphopenia

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 t...

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Veröffentlicht in:JCI insight Jg. 4; H. 12
Hauptverfasser: Coles, Alasdair J., Azzopardi, Laura, Kousin-Ezewu, Onajite, Mullay, Harpreet Kaur, Thompson, Sara A.J., Jarvis, Lorna, Davies, Jessica, Howlett, Sarah, Rainbow, Daniel, Babar, Judith, Sadler, Timothy J., Brown, J. William L., Needham, Edward, May, Karen, Georgieva, Zoya G., Handel, Adam E., Maio, Stefano, Deadman, Mary, Rota, Ioanna, Holländer, Georg, Dawson, Sarah, Jayne, David, Seggewiss-Bernhardt, Ruth, Douek, Daniel C., Isaacs, John D., Jones, Joanne L.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 20.06.2019
Schlagworte:
Adolescent
Adult
Animals
CD4-Positive T-Lymphocytes - immunology
CD52 Antigen - metabolism
Clinical Medicine
Disease Models, Animal
Female
Fibroblast Growth Factor 7 - pharmacology
Fibroblast Growth Factor 7 - therapeutic use
Humans
Lymphopenia - drug therapy
Male
Mice
Middle Aged
Multiple Sclerosis, Relapsing-Remitting - immunology
Young Adult
T cell development
Immunology
Autoimmune diseases
T cells
Therapeutics
ISSN:2379-3708, 2379-3708
Online-Zugang:Volltext
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Zusammenfassung: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. 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 signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30. 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 protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: 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. ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation.
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ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.125377