Theiler's murine encephalomyelitis virus (TMEV) produces a persistent infection in its natural host, the mouse. During the chronic phase of the infection the most prominent pathological feature is the production of multiple areas of inflammatory demyelination in a pattern which closely recalls that observed in human multiple sclerosis (MS). The pathogenesis of myelin destruction in this model is still unknown, and its elucidation would be important since the TMEV model is now considered as one of the best experimental models of MS. We have been investigating this model for several years and considerable progress in the understanding of this infection has been made both in our and other laboratories. Of particular importance are findings indicating that the demyelinating pathology is mediated through the host immune response, rather than being due to direct viral killing. In addition, it has become clear that the susceptibility to the infection is genetically controlled at the level of multiple genes, both in, and outside the MHC Finally, and most importantly, the immunological parameter that best correlates with susceptibility to demyelination is the ability of a given murine strain to develop a DTH response to the virus after intracerebral inoculation. This strongly suggest that the brunt of myelin destruction in this model may be produced as an effect of the DTH response to the virus. Liberation of soluble effector products, therefore, should be an important component of this pathogenetic pathway. This proposal has four specific aims.
Aim # 1 seeks to elucidate the type of cells which are susceptible to TMEV infection and capable of maintaining the infection for the life of the animal. Such studies will utilize spinal cord and isolated glial cells from infected animals as well as isolated glial cells and organotypic cultures to be infected in vitro. Both immunohistochemistry and in situ hybridization will be used for these studies.
Aim #2 will address the localization of the most important cytokines during various phases of the infection in strains of different susceptibility to demyelination. In addition we shall try to interfere with the activity of such cytokines and explore the effects of their inoculation in the disease process.
With Aim #3 we shall try to intervene in a negative fashion on the development of the DTH response by tolerizing animals to TMEV and its DTH driving peptides. A down-regulation of the disease process would be expected in such experiments. By contrast, in Aim #4, we shall intervene on the DTH response in a positive fashion by injecting pure T cell clones against such peptides into the CNS of sub-clinically infected susceptible animals and cultures and into resistant murine hybrids. The inoculation of these peptides should boost the DTH response thus precipitating disease in susceptible animals and cultures sub-optimally infected, and in hybrids between resistant and susceptible animals in which suppressor functions would normally impede the manifestation of disease. With this proposal we hope to further clarify the role that TMEV and the DTH response to some of its capsid peptides may play in the pathogenesis of demyelination in this important model of MS.
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