In the human demyelinating disorder multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE), there is a breakdown of the blood-brain barrier and an infiltration of immune cells into the CNS. Infiltrating T lymphocytes and macrophages are believed to be key mediators of the disease process. Considerable circumstantial and experimental evidence has suggested that the pleiotropic cytokine interferon gamma (IFN-gamma), which is exclusively expressed by T cells and natural killer cells, is a deleterious component of the immune response in these disorders. We have shown that when ectopically expressed in the CNS of transgenic animals IFN-y promotes many of the pathological changes that occur in immune-mediated demyelinating disorders. The harmful actions of IFN-gamma on CNS myelin are likely mediated, at least in part, through direct effects on the myelinating cells. In support of this hypothesis we have shown that this cytokine elicits a number of effects on oligodendrocytes in vitro, including their apoptotic cell death. We have shown also generated in vivo data that suggests that one detrimental effect of IFN-gamma involves overloading the endoplasmic reticulum (ER) of oligodendrocytes through the induction of major histocompatibility complex (MHC) class I heavy chain gene expression. In the current application we plan to build on these studies to further explore the role that this cytokine plays in immune-mediated demyelinating disorders. We will establish second generation transgenic animals, using the tetracycline-induction system that will allow us to control IFN-gamma delivery into the CNS. Using these animals we will examine the effect of the presence of IFN-gamma on the remyelination process exploiting the cuprizone model of demyelination. We will also examine whether members of a newly discovered family of proteins, termed suppressors of cytokine signaling (SOCS), are able to protect oligodendrocytes from the deleterious actions of IFN-gamma. Moreover, we will examine biochemically and genetically the possibility that the primary effect of IFN-gamma on oligodendrocytes is mediated through the induction of ER stress. Together, these studies will significantly further our understanding of the cellular and molecular effects of immune cell infiltration into the CNS. Such information is critical to the rationale design of therapeutic strategies.
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