Antigen-shift in varicella-zoster virus-specific T-cell immunity over the course of Fingolimod-treatment in relapse-remitting multiple sclerosis patients

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 CC 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: Fingolimod; IE62/IE63/ORF26; Multiple sclerosis; T-cell immunity; Varicella-zoster virus.