Keratinocyte growth factor impairs human thymic recovery from lymphopenia.

Abstract

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation.

• Authors: Alasdair J Coles, Laura Azzopardi, Onajite Kousin-Ezewu, Harpreet Kaur Mullay, Sara Aj 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
• Journal: JCI insight (JCI Insight) Vol. 5 (05 07 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31063156 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• CD52 Antigen
• Fibroblast Growth Factor 7

Topics

• Adolescent
• Adult
• Animals
• CD4-Positive T-Lymphocytes (immunology)
• CD52 Antigen (metabolism)
• Disease Models, Animal
• Female
• Fibroblast Growth Factor 7 (pharmacology, therapeutic use)
• Humans
• Lymphopenia (drug therapy)
• Male
• Mice
• Middle Aged
• Multiple Sclerosis, Relapsing-Remitting (immunology)
• Young Adult