CD56 ^bright natural killer cells and response to daclizumab HYP in relapsing-remitting MS

Abstract

Objective:To assess the relationship between CD56bright natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP).Methods:Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56bright NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate.Results:In DAC HYP–treated patients but not placebo-treated patients, the numbers of CD56bright NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56bright NK cell counts and the annualized relapse rate in DAC HYP–treated patients. DAC HYP–treated patients who showed lower levels of expansion of CD56bright NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment.Conclusions:CD56bright NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes.

Human CD56bright NK Cells: An Update

“…In this context, the increase in circulating CD56 bright NK cells is associated with preferential IL-2 signaling through IL-2R, decreased brain inflammation, and reduced survival of activated T cells (104). Indeed, the expanded CD56 bright NK cells after treatment with CD25-blocking Ab kill autologous activated T cells in vitro (105,106). The mechanisms behind this include the degranulation of granzymes A and K, followed by activation of a caspaseindependent apoptosis that induces a mitochondrial dysfunction in activated T cells (107).…”

A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis

“…While this analysis confirms that individual variability in CD56 bright NK cell counts after treatment with DAC-HYP contains some prognostic information, their relationship to DAC-HYP response is complex and does not appear to translate directly into simple classifications such as 'responders' and 'non-responders' [36]. Nevertheless, these findings support the biological relevance of these cells to the effects of DAC-HYP on MS, and additional phenotypic characterization of CD56 bright NK cells should be considered as a way to better understand individual variation in the treatment response to DAC-HYP.…”

Steering through complexity

“…Interestingly, a type of suppressor cell induced by daclizumab, the NK56 bright cells that are measured by flow cytometry of peripheral blood, has initially been proposed to track with therapeutic efficacy. Biomarkers of therapeutic efficacy for any multiple sclerosis therapy have thus far been elusive, and it is not obvious that monitoring for NK56 bright cells in daclizumab-treated patients will be clinically useful [37]. This product will likely be placed as a secondline therapy in the multiple sclerosis armamentarium given that monthly LFT monitoring is expected to be required in clinical practice.…”