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The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cuprizone and discuss the molecular and enzymatic mechanisms by which cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following cuprizone treatment, and how these strengthened the cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.

Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8 + T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-γ-producing CD8 + T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients.cancer vaccine | active specific immunotherapy | phase I clinical trial

After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT