Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by the human polyomavirus, JC virus (JCV). PML, once a rare disease of the elderly, is most frequency seen in AIDS patients and has more recently occurred in other severely immunosuppressed patients, including those on immunosuppressive therapy for the treatment of multiple sclerosis, Crohn's disease, rheumatoid arthritis, and B cell lymphomas. It is believed that immunosuppression with potent new classes of immunosuppressive agents, including the anti-CD20 molecule, rituximab, allows JC virus to replicate in patients which leads to the development of PML. We hypothesize that rituximab may indirectly lead to the development of PML by causing the release of certain cytokines or other soluble mediators which trigger JCV replication in infected astrocytes. In support of this hypothesis, our preliminary data found that conditioned media harvested from PBMCs treated with rituximab increased JCV replication in astrocytes. We have also detected upregulation of cytokines, extracellular matrix proteins, and other cellular factors by microarray analysis of JCV infected astrocytes and immunohistochemistry of PML brain tissue which further supports this hypothesis. In this study, we propose a set of cell biology and immunobiology experiments aimed at determining the effect of rituximab on immune regulation of JCV and virus reactivation through direct and indirect methods. We will examine the effect of B cell and T cell treatment with rituximab and the profile of cytokines and chemokines produced by this treatment. We will then examine the effect of these cytokines on JCV infected astrocytes to determine which immunomodulators are responsible for upregulation of JCV. Through the proposed studies, we will elucidate key chemokines and cytokines which affect JCV activity and how potent immunosuppressive therapies may cause reactivation of JCV in the brain leading to the fatal demyelinating disease, PML.
The demyelinating disease, progressive multifocal leukoencephalopathy (PML), is a deadly complication seen in patients with autoimmune disorders including multiple sclerosis, rheumatoid arthritis, and lupus, who are being treated with powerful immunosuppressive therapies, including Tysabri and Rituximab. Our study will determine what immunomodulators are produced by the immunosuppressive drugs that lead to increased replication of JC virus, the virus that causes PML, and will help us to understand which patients are at risk for developing this demyelinating disease.
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