Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia

Caruana, Patricia; Lemmert, Karla; Ribbons, Karen; Lea, Rodney Arthur; Lechner‐Scott, Jeannette

doi:10.1177/1352458516679267

Cited by 31 publications

(29 citation statements)

References 33 publications

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“…Our results support previous findings that peripheral blood from people with MS has fewer CD56bright NK cells than HC [4]. Other findings have been reported; CD56bright NK cells were increased in blood from people with RRMS with no disease-associated MRI changes over 2.4 years [5]. CD56 bright NK cells can have multiple functions, including production of cytokines such as IFN-γ, IL-10 and TNF-β, as well as cytotoxic and regulatory activities in T cell responses [5,6].…”

Section: Discussionsupporting

confidence: 92%

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Trend

Jones

Geldenhuys

et al. 2017

IJMS

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It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS.

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Section: Discussionsupporting

confidence: 92%

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Trend

Jones

Geldenhuys

et al. 2017

IJMS

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“…NK bright and invariant NKT cells, a subset of NKT, are often related to regulatory processes ( 46 ). In MS patients, a high proportion of NK bright cells has recently been associated with stable MRI ( 47 ), and we found that a higher percentage of these cells before treatment was associated with a good response and that they decreased to a lesser degree after treatment in responder compared with NR patients. In our study, fingolimod not only increased the percentage of NK cells but it also upregulated NCAM1 (CD56) and FCGR3A (CD16a) at the transcriptional level; an enrichment of the NK and innate response pathways was also observed as a result of the therapy.…”

Section: Discussionsupporting

confidence: 51%

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Torres

Garcı́a²,

Marconi

et al. 2018

Front. Immunol.

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BackgroundFingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment.Materials and methodsSamples were obtained from relapsing–remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics.ResultsFingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod.ConclusionMS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.

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“…The deep profiling of NK cells performed here, including in the placebo group, can also serve as a reference for future studies of NK cell phenotype in the setting of RMS. While daclizumab beta was voluntarily withdrawn from the market due to serious adverse events, it is notable that several other medications used to treat RMS, including natalizumab, fingolimod, glatiramer acetate, or beta interferon, are also associated with expanded CD56 bright NK cells in the setting of clinical response (53). Thus, in order to improve treatment for RMS, it will be critical in future studies to determine whether specific features of NK cells are associated with clinical response or serious adverse events.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Impact of Daclizumab Beta on Circulating Natural Killer Cells by Mass Cytometry

et al. 2020

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Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing forms of multiple sclerosis (RMS), daclizumab beta induces robust expansion of the CD56 bright subpopulation of NK cells that is correlated with the drug's therapeutic effects. As NK cells represent a heterogeneous population of lymphocytes with a range of phenotypes and functions, the goal of this study was to better understand how daclizumab beta altered the NK cell repertoire to provide further insight into the possible mechanism(s) of action in RMS. We used mass cytometry to evaluate expression patterns of NK cell markers and provide a comprehensive assessment of the NK cell repertoire in individuals with RMS treated with daclizumab beta or placebo over the course of 1 year. Treatment with daclizumab beta significantly altered the NK cell repertoire compared to placebo treatment. As previously reported, daclizumab beta significantly increased expression of CD56 on total NK cells. Within the CD56 bright NK cells, treatment was associated with multiple phenotypic changes, including increased expression of NKG2A and NKp44, and diminished expression of CD244, CD57, and NKp46. These alterations occurred broadly across the CD56 bright population, and were not associated with a specific subset of CD56 bright NK cells. While the changes were less dramatic, CD56 dim NK cells responded distinctly to daclizumab beta treatment, with higher expression of CD2 and NKG2A, and lower expression of FAS-L, HLA-DR, NTB-A, NKp30, and Perforin. Together, these data indicate that the expanded CD56 bright NK cells share features of both immature and mature NK cells. These findings show that daclizumab beta treatment is associated with unique changes in NK cells that may enhance their ability to kill autoreactive T cells or to exert immunomodulatory functions.

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Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia

Abstract: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

Cited by 31 publications

References 33 publications

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Characterization of the Impact of Daclizumab Beta on Circulating Natural Killer Cells by Mass Cytometry

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