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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Vydáno v:	JCI insight Ročník 4; číslo 12
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 20.06.2019
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.125377