Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells

Abstract

Fingolimod is an approved oral treatment for relapsing–remitting multiple sclerosis (RRMS) that modulates agonistically the sphingosin-1-phosphate receptor (S1PR), inhibiting thereby the egress of lymphocytes from the lymph nodes. In this interventional prospective clinical phase IV trial, we longitudinally investigated the impact of fingolimod on frequencies of NK cell subpopulations by flow cytometry in 17 RRMS patients at baseline and 1, 3, 6, and 12 months after treatment initiation. Clinical outcome was assessed by the Expanded Disability Status Scale (EDSS) and annualized relapse rates (ARR). Over the study period, median EDSS remained stable from month 3 to month 12, and ARR decreased compared to ARR in the 24 months prior treatment. Treatment was paralleled by an increased frequency of circulating NK cells, due primarily to an increase in CD56dimCD94low mature NK cells, while the CD56bright fraction and CD127+ innate lymphoid cells (ILCs) decreased over time. An unsupervised clustering algorithm further revealed that a particular fraction of NK cells defined by the expression of CD56dimCD16++KIR+/−NKG2A−CD94−CCR7+/−CX3CR1+/−NKG2C−NKG2D+NKp46−DNAM1++CD127+ increased during treatment. This specific phenotype might reflect a status of aged, fully differentiated, and less functional NK cells. Our study confirms that fingolimod treatment affects both NK cells and ILC. In addition, our study suggests that treatment leads to the enrichment of a specific NK cell subset characterized by an aged phenotype. This might limit the anti-microbial and anti-tumour NK cell activity in fingolimod-treated patients.

Immunophenotyping in routine clinical practice for predicting treatment response and adverse events in patients with MS

“…It is well established that DMDs change the cellular immune profile in pwMS ( 17 ). Prior studies have implicated a predictive value of pre-treatment or on-treatment cellular subsets in predicting relapses and/or AEs ( 3 , 7 , 18 , 19 ). While most studies use peripheral blood mononuclear cells (PBMCs) due to their ability to be frozen and stored, studies in fresh blood in the standardized clinical certified laboratory are rare ( 20 ).…”

Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis

“…To yield deeper understanding of the role of NK cells during pregnancy in MS, analyses need to go beyond monitoring the prototypic NK cell phenotypes of CD56 bright and CD56 dim . This becomes apparent in light of new data that reveal a far more complex phenotypic and functional diversity of human NK subsets that may be relevant for health and disease ( 33 , 34 ). Here, we provided first in-depth profiling of the NK cell phenotype in MS pregnancy showing that the expansion of CD56 bright NK cells may be driven by a CD16 + NKp46 high NKG2D high NKG2A high subset.…”

The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy

“…When NKG2D was blocked, the number and motility of CD8 + T cells co-cultured with astrocytes expressing NKG2D-L were increased, suggesting that NKG2D was involved in the interaction between CD8 + T cells and astrocytes [83]. In the treatment of MS patients, different drugs are used, such as interferonβ (IFN-β) and Fingolimod [84][85][86]. Patients with relapsing multiple sclerosis (RR-MS) under IFN-β treatment were found to have significantly increased levels of both NKG2D, an activating receptor on the surfaces of NK cells, and interleukin-22 (IL-22), suggesting that IFN-β treatment directs NK cells toward a pro-inflammatory state [84].…”