Induction of apoptosis in CD4(+) T-cells is linked with optimal treatment response in patients with relapsing-remitting multiple sclerosis treated with Glatiramer acetate

Published:March 29, 2019DOI:https://doi.org/10.1016/j.jns.2019.03.030

      Highlights

      • Induction of T-cell apoptosis constitutes a mechanism of action for Glatiramer Acetate (GA).
      • Reduced T-cell apoptosis under GA correlates with increased radiological activity.
      • T-cell apoptosis may be a biomarker for optimal treatment response under GA.

      Abstract

      Background

      Induction of T-cell apoptosis constitutes a mechanism of action for Glatiramer Acetate (GA). We investigated whether activation of apoptotic T-cell death may be indicative of optimal treatment response in patients with relapsing-remitting Multiple Sclerosis (RRMS), with respect to radiological activity.

      Methods

      We studied apoptotic markers on blood T-cells of forty patients with RRMS, 19 patients under GA and 21 patients under interferon-β (IFNβ), by flow cytometry. Patients were relapse-free and were further classified into optimal and sub-optimal responders based on radiological activity. Eighteen patients (8 patients under GA and 10 patients under IFNβ were additionally evaluated at a 12-month follow-up and were relapse- and radiological activity-free. For these patients, apoptosis was also evaluated by molecular techniques.

      Results

      At inclusion, optimal responders to GA exhibited increased (23.6 ± 1.976) relative % frequency of CD4(+)AnnexinV(+)7AAD(−) T-cells, compared to sub-optimal responders (14.478 ± 1.204, p = 0.001). Similarly, relative % frequency of caspase-3(+) T-cells was 1.517 ± 0.436 versus 0.45 ± 0.149 (p = 0.041), respectively. Anti-apoptotic molecule bcl-2 showed an inverse pattern 4.532 ± 1.321 versus 13.094 ± 3.987, p = 0.044, respectively. These differences were not evident for IFNβ-treated patients.

      Conclusions

      T-cell apoptotic markers may be applied as a biomarker useful in evaluating optimal treatment response under GA, thus allowing for personalized treatment decisions.

      Graphical abstract

      Keywords

      Abbreviations:

      GA (Glatiramer acetate), IFNβ (interferon-β), PBMCs (peripheral blood mononuclear cells), NEDA (No Evidence of Disease Activity), EDSS (Expanded Disability Status Scale), MSFC (Multiple Sclerosis Functional Composite), TNF (tumor necrosis factor), TRAIL (TNF-related apoptosis inducing ligand), MBP (myelin basic protein), Th1 (T-helper type-1), Th2 (T-helper type-2), Bax (Bcl-2-associated X protein), Card4 (caspase activation and recruitment domain family - member 4), Casp3 (caspase 3), Casp9 (caspase 9), Cse1L (cellular apoptosis susceptibility gene), Dapk3 (death-associated protein kinase 3), DR3 (death receptor 3), DR6 (death receptor 6), Gorasp1 (golgi reassembly-stacking protein 1), Madd (MAP-kinase activating death domain)
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