T-cell response against varicella-zoster virus in fingolimod-treated MS patients

Objective: To study the immune response against varicella-zoster virus (VZV) in patients with multiple sclerosis before and during fingolimod therapy. Methods: The VZV-specific immune response was studied using interferon (IFN)-gamma enzyme-linked immunosorbent spot assay, proliferation assays, and upregulation of T-cell activation markers in patients before (n = 38) and after 3 months of fingolimod therapy (n = 34), in untreated (n 5 33) and IFN-beta-treated (n = 25) patients with multiple sclerosis, and in healthy controls (n 5 22). Viral replication was analyzed by using real-time PCR in 76 peripheral blood mononuclear cell samples and 146 saliva samples. Results: Treatment with fingolimod led to a marked reduction of CD3(+) T cells with a relative decrease of naive and central memory T cells and an increase of effector memory T cells. Expression of the activation markers CD137 and CD69 upon VZV stimulation was unaltered by fingolimod. However, the absolute number of cells proliferating upon VZV stimulation was reduced in the blood of patients treated with fingolimod. Also, VZV-specific and Epstein-Barr virus (EBV)-specific IFN-gamma-producing cells were reduced after fingolimod therapy. Seven of the 35 patients treated with fingolimod showed signs of VZV or EBV reactivation in saliva compared with 3 of the 111 controls. None of the 76 tested samples showed signs of viral reactivation in the peripheral blood mononuclear cells. Conclusion: Patients treated with fingolimod show a slightly reduced antiviral T-cell response. This reduced response is accompanied by a subclinical reactivation of VZV or EBV in the saliva of 20% of patients treated with fingolimod.