@article{10.1172/jci.insight.125377, author = {Alasdair J. Coles AND Laura Azzopardi AND Onajite Kousin-Ezewu AND Harpreet Kaur Mullay AND Sara A.J. Thompson AND Lorna Jarvis AND Jessica Davies AND Sarah Howlett AND Daniel Rainbow AND Judith Babar AND Timothy J. Sadler AND J. William L. Brown AND Edward Needham AND Karen May AND Zoya G. Georgieva AND Adam E. Handel AND Stefano Maio AND Mary Deadman AND Ioanna Rota AND Georg Holländer AND Sarah Dawson AND David Jayne AND Ruth Seggewiss-Bernhardt AND Daniel C. Douek AND John D. Isaacs AND Joanne L. Jones}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Keratinocyte growth factor impairs human thymic recovery from lymphopenia}, year = {2019}, month = {6}, volume = {4}, url = {https://insight.jci.org/articles/view/125377}, 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.}, number = {12}, doi = {10.1172/jci.insight.125377}, url = {https://doi.org/10.1172/jci.insight.125377}, }