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Keratinocyte growth factor impairs human thymic recovery from lymphopenia

Lookup NU author(s): Professor John Isaacs

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Abstract

© 2019 American Society for Clinical Investigation. All rights reserved.Background. The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS); however, 50% of patients develop novel autoimmunity after 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 nonhuman primates. Methods. Following a dose tolerability substudy, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5.0, with ≥2 relapses in the previous 2 years) were randomized to placebo or 180 μg/kg/d palifermin, given for 3 days immediately before and after each cycle of alemtuzumab, with repeat doses at month 1 (M1) and M3. The interim primary endpoint was naive CD4+ T cell count at M6. Exploratory endpoints included number of recent thymic emigrants (RTEs) and signal joint T cell receptor excision circles/ml (sjTRECs/ml) of blood. The trial's primary endpoint was incidence of autoimmunity at M30. Results. At M6, individuals receiving palifermin had fewer naive CD4+ T cells (2.229 × 107/l vs. 7.733 × 107/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 2 groups. Conclusion. In contrast with 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/hematology setting, where alemtuzumab is often used as part of the conditioning regime.


Publication metadata

Author(s): Coles AJ, Azzopardi L, Kousin-Ezewu O, Mullay HK, Thompson SAJ, Jarvis L, Davies J, Howlett S, Rainbow D, Babar J, Sadler TJ, Brown JWL, Needham E, May K, Georgieva ZG, Handel AE, Maio S, Deadman M, Rota I, Hollander G, Dawson S, Jayne D, Seggewiss-Bernhardt R, Douek DC, Isaacs JD, Jones JL

Publication type: Article

Publication status: Published

Journal: JCI Insight

Year: 2019

Volume: 4

Issue: 12

Print publication date: 20/06/2019

Online publication date: 07/05/2019

Acceptance date: 01/05/2019

Date deposited: 29/08/2019

ISSN (print): 2379-3708

Publisher: American Society for Clinical Investigation

URL: https://doi.org/10.1172/jci.insight.125377

DOI: 10.1172/jci.insight.125377

PubMed id: 31063156


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