Keratinocyte growth factor impairs human thymic recovery from lymphopenia

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 × 10 7 /l vs. 7.733 × 10 7 /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.

T cell regeneration after immunological injury

“…As demonstrated in previous preclinical work 158 , the benefits of palifermin on immune reconstitution in transplant recipients may derive from its synergistic effects with other immune-boosting therapies rather than as a sole therapeutic agent. However, a recent study of the use of KGF to promote immune reconstitution in patients with relapsing–remitting multiple sclerosis treated with the anti-CD52 lymphocyte-depleting agent alemtuzumab showed reduced thymic output in KGF-treated patients as measured by evaluation of naive CD4 + T cells, RTEs and TRECs (NCT01712945) 159 . Given that human cTECs express CD52, one possible explanation for these clinical data is that palifermin exacerbates the negative effects of alemtuzumab on thymic function, perhaps through upregulation of CD52 expression on cTECs, rendering these cells more susceptible to antibody-mediated elimination.…”

When the Damage Is Done: Injury and Repair in Thymus Function

“…Furthermore, pre-conditioning with KGF prior to bone marrow transplantation reduces GVHD in mouse models by protecting against epithelial injury ( 113 ). However, a recent clinical trial noted a reduction in thymopoiesis in lymphopenic patients following administration of KGF ( 114 ), highlighting that more studies need to be carried out before KGF can be used across the board as a therapeutic regulator of thymic regeneration.…”

Generation and Regeneration of Thymic Epithelial Cells

“…In addition, frequencies of RTE were reduced following treatment with palifermin up to 6 months later. CD4 + effector memory cells were increased post-palifermin suggesting decrease in TCR repertoire (104). Despite improved thymopoiesis in murine models, KGF treatment in clinical trials has not improved T cell reconstitution, suggesting different requirements for KGF mediated TEC recovery in humans.…”