There is strong evidence that chronic permanent neurologic impairment in multiple sclerosis is the result of injury and potential loss of axons. We have shown in a viral model of multiple sclerosis induced by Theiler's virus that the immune response contributes to neurologic deficits and axonal dropout months following demyelination of the spinal cord. In this set of experiments we will test the hypothesis that axonal loss which follows demyelination can be the result of immune-mediated damage to axons. Although we have striking data demonstrating the expression of Class I molecules on neurons and axons under pathologic conditions, there is still significant controversy regarding the expression of MHC on CNS cells. Our hypothesis depends in part on the expression of these proteins in the CNS during chronic demyelination. Thereforethe first goal of this project is to examine, using double and triple labeling con-focal immunofluorescence, the expression of MHCClass I and MHCClass II on CNScells with a particular focus on neurons and axons. We will also examine the interaction of MHC molecules on CNS cells with CD8+ T cells, CD4+T cells, NK cells, macrophages, and perforin in the spinal cords of animals with chronic demyelination induced by Theiler's virus infection and in myelin mutant mice with denuded axons. The second goal is to quantify immune mediated axonal loss and changes in neurologic function by adoptive transfer experiments using purified populations of antigen-specific and non antigen-specific immune cells into mice with chronic demyelination either induced by virus or mutations that lead to spontaneous dysmyelination. The third goal is to develop transgenic mouse models in which neurons are specifically deficient in MHCclass I function or in which MHC class I function is only expressed on neurons, andto characterize axonal injury following Theiler's virus infection in these animals. These experiments will specifically address whether immune cells require the direct engagement of MHC molecules for induction of axonal injury. The findings are expected to provide new insights into the pathogenesis of axonal and neuronal injury in demyelinating disorders such as multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032129-15
Application #
7746347
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
1994-08-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
15
Fiscal Year
2010
Total Cost
$320,109
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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