The human disease multiple sclerosis in an autoimmune demyelinating disease of the central nervous system (CNS) and is thought to be initiated by CD4 Th1 cells with specificity for self-antigens present in the myelin sheath. Antigen presentation of the self-antigens is believed to be necessary for the propagation of disease. The cell(s) that present the antigen is currently not known. A candidate cell is the microglial cell that is considered to be a """"""""fixed"""""""" macrophage system within the CNS. Resting microglial cells have a distinct ramified morphology and are poor antigen presenting cells (APC) by virtue of low expression levels of MHC class II and costimulatory molecules. Under a variety of pathological conditions microglial cells have shown the capacity to differentiate into """"""""macrophage-like"""""""" cells as indicated by a change in morphology and by the upregulation of CD45, MHC class II and costimulatory molecules. Whether microglial cells differentiate and become activated during MS is not known. This proposal will investigate the differentiation and activation of microglial cells in the CNS using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE recapitulates much of the pathology of MS including the presence of an inflammatory infiltrate in the CNS comprised primarily of macrophages. In addition, EAE to a certain extent mimics the paralysis observed in MS patients. By monitoring the extent of the neurological symptoms the severity of disease can be determined. This proposal will examine whether the self-reactive encephalitogenic T cell can signal the differentiation and activation of microglial cells. The following hypothesis will be tested: Antigen presentation by microglial cells in the CNS is necessary for the onset of EAE and the signals required for differentiation of microglial cells into effective APC can be provided exclusively by encephalitogenic T cells. This hypothesis will be tested by two specific aims.
Aim 1 : The stages and kinetics of microglial cell differentiation during EAE will be determined using BM chimera mice that will allow the distinction between activated microglial cells and peripheral macrophages that currently is not possible by phenotype.
Aim 2 : The role of encephalitogenic derived signals in the activation of microglial cells in vivo during CNS pathology will be examined using EAE as the model. T cell derived growth factors and costimulation as well as the requirement for antigen presentation will be examined. These studies will determine whether microglial cells become activated in the CNS during EAE and the extent of encephalitogenic T cell involvement. In addition, these studies should be directly applicable to MS pathology and hopefully will lead to improved therapeutics for MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046662-03
Application #
7022211
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Utz, Ursula
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$302,544
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
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