Abstract
Progressive multifocal leukoencephalopathy (PML) induced by JC virus (JCV) is a risk for natalizumab-treated multiple sclerosis (MS) patients. Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MS patients to reveal functional differences that may account for the development of natalizumab-associated PML. CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MS patients and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MS patients with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML. Thus, natalizumab-treated MS patients with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated patients.
Highlights
Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by JC virus (JCV) [1]
Responses were measured by intracellular cytokine staining (ICS) and polychromatic flow cytometry for cytokines associated with effective control of viral infections: IFNc, tumor necrosis factor (TNF) and interleukin 2 (IL-2), and for a cytokine associated with poor control of viral infections [25,26,27], interleukin 10 (IL-10)
In order to determine whether multiple sclerosis (MS) patients with natalizumabassociated Progressive multifocal leukoencephalopathy (PML) had similar T cell responses, we examined the response to mitogenic stimulation in T cells from four patients whose cerebrospinal fluid (CSF) samples were previously tested in our laboratory for JCV DNA
Summary
Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by JC virus (JCV) [1]. The mechanism underlying JCV reactivation in natalizumab-treated individuals with MS is actively being investigated, but may involve both reduced immune surveillance of the central nervous system due to attenuated extravasation of leukocytes out of the bloodstream and into tissues [5,6,7], and latent viral infection in CD34+ cells that migrate from the bone marrow to the peripheral circulation [8] In this context, characterization of the effects of natalizumab on T cell immune control of JCV replication might shed light on the host and viral factors that determine the risk for the development of PML
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