Changes in JC Virus-Specific T Cell Responses during Natalizumab Treatment and in Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

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. Progressive multifocal leukoencephalopathy (PML) is a complication of treatment with natalizumab in patients with multiple sclerosis (MS) and Crohn's disease. PML results from a failure of the immune system to control replication of JC virus (JCV) in the brain. We studied the T cell responses of 8 patients with MS who were starting treatment with natalizumab, 10 healthy volunteers, and 4 patients with natalizumab-associated PML. The magnitude and quality of JCV-specific immune responses remained unchanged after starting natalizumab. However, applying the same methods and antigens, we found that immune responses in the individuals who developed PML differed from those in the MS patients and healthy volunteers. In the four patients with PML from whom the laboratory had identified JCV DNA in the cerebrospinal fluid (CSF), two had no measurable T cell response to JCV and two had T cells that produced IL-10, an anti-inflammatory mediator. Furthermore, we studied the CSF of 10 patients with natalizumab-associated PML and 10 patients on natalizumab who had similar symptoms but did not have PML. We found that IL-10 was detectable in the CSF of half of the individuals with PML but none of the control group. These findings shed light on the mechanisms that lead to PML in a subset of patients treated with natalizumab and have implications for therapeutic and preventative measures.