Keratinocyte growth factor impairs human thymic recovery from lymphopenia

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Abstract

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 protocol-defined 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.TRIAL REGISTRATION ClinicalTrials.gov NCT01712945.FUNDING MRC and Moulton Charitable Trust.

Authors

Alasdair J. Coles, Laura Azzopardi, Onajite Kousin-Ezewu, Harpreet Kaur Mullay, Sara A.J. Thompson, Lorna Jarvis, Jessica Davies, Sarah Howlett, Daniel Rainbow, Judith Babar, Timothy J. Sadler, J. William L. Brown, Edward Needham, Karen May, Zoya G. Georgieva, Adam E. Handel, Stefano Maio, Mary Deadman, Ioanna Rota, Georg Holländer, Sarah Dawson, David Jayne, Ruth Seggewiss-Bernhardt, Daniel C. Douek, John D. Isaacs, Joanne L. Jones