Highlights
- •decrease of circulating CCR7+ T cells over the course of FTY-treatment.
- •increase of VZV-specific CD8+ T cell immunity following FTY-treatment.
- •shift of the VZV-specific CD8+ T-cell immunity from IE62/IE63 to ORF26.
- •correlation between VZV-specific IgG serum titer and VZV-specific T-cell immunity.
ABSTRACT
Background
Fingolimod (FTY) applied as treatment regimen of relapsing-remitting multiple sclerosis
(RRMS) induces downregulation of sphingosine-1-phosphate receptors on the lymphocytes.
As a result C C chemokine receptor type 7 (CCR7) expressing lymphocytes are retained within the
peripheral lymph nodes thus suppressing their accumulation into the cerebrospinal
fluid of multiple sclerosis (MS) patients and hampering disease progress. Unfortunately,
MS patients treated with FTY suffer from an increased incidence of varicella-zoster
virus (VZV) infections which has been associated with a decrease of VZV immediate
early 63 (IE63)-specific T-cell immunity.
To elucidate VZV-specific T-cell immunity over the course of FTY-treatment, we analyzed
T-cell immunity for immediate early, early and late VZV-antigens.
Methods
T-cell immune responses were detected via intracellular IFN-γ staining after stimulation
with VZV-specific peptide mixes for IE62 and IE63 and recombinant proteins for open
reading frame 26 (ORF26), ORF9 and glycoprotein E (gE) using flow cytometry. Analyzed
samples comprised of different groups including 18 patients with RRMS at baseline
(BL), 6 and 12 months after FTY-treatment start, 12 patients with long-term (LT) FTY-treatment,
one FTY-treated patient, before and after VZV-reactivation. In addition, VZV-specific
IgG and IgM titers were assessed by ELISA.
Results
After FTY-treatment start, absolute numbers of CCR7 expressing CD4+ T cells and CD8+T cells dropped rapidly. However, VZV-specific immunity could be detected in the majority
of RRMS patients throughout FTY-treatment with increasing prevalence after 6 months
of treatment. We found an increase in the prevalence of VZV-specific IFN-γ+CD8+ T-cell immunity in FTY-treated patients after six months of therapy, while in parallel
VZV-specific IFN-γ+CD4+ T cells declined dramatically. Additionally, a strong correlation between VZV-specific
IgG serum titers and the percentage of RRMS patients with detectable VZV-specific
T cells was observed (r = 0.985).
Most remarkably, FTY-treated RRMS patients presented a shift in the predominant CD8+ T cell-mediated antigen-response from immediate early (IE62) to early virus antigens
(ORF26) six months after treatment in parallel to a decrease of VZV-specific CD4+ T-cell immunity. ORF26-specific CD8+ T cells still dominated the VZV-specific cellular immunity at month 12 after FTY-treatment
start and in LT FTY-treated MS patients. In a RRMS patient an increase of VZV-specific
CD4+ T cells at VZV-reactivation accompanied with a four-fold increase of a VZV-specific
IgG titer was detected which might indicate an important role in cellular immune control
of VZV-infections.
Conclusion
Monitoring VZV-specific T-cell immunity might provide a valuable tool to RRMS patient
risk management during FTY-treatment.
Keywords
Abbreviations:
BL (Baseline), CCR7 (C-C chemokine receptor 7), EMA (ethidium monoazide), FACS (fluorescence activated cell sorting), FTY (fingolimod), gE (glycoprotein E), HI (healthy individuals), HSA (human serum albumin), HZ (herpes zoster), IE (Intermediate early), Ig (Immunoglobulin), INF-γ (interferon gamma), MS (multiple sclerosis), LT (long-term), ORF (open reading frame), PBMC (peripheral blood mononuclear cells), RRMS (Relapse-remitting multiple sclerosis), TCM (central memory T cells), TEff (Effector T cells), TEM (effector memory T cells), VZV (varicella-zoster virus)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: November 16, 2019
Accepted:
November 15,
2019
Received in revised form:
October 22,
2019
Received:
May 22,
2019
Identification
Copyright
© 2019 Elsevier B.V. All rights reserved.
