The experimentally-induced autoimmune disease, experimental allergic encephalomyelitis (EAE), is the consequence of an inflammatory process initiated by the interaction of neuroantigen-specific T cells with antigenic peptides presented by MHC class II+ antigen presenting cells (APC) in the CNS. The dynamics of the CNS T cell population during acute and relapsing EAE is an important aspect of this disease particularly with respect to the design of immunotherapeutic protocols. An important issue is the mechanism by which the encephalitogenic activity of neuroantigen-specific T cells is regulated in the normal animal as well as during the course of chronic relapsing EAE. We have found that normal regulatory activity is absent in TCR beta-chain knockout (alpha/betaTCR-/-) mice. Preliminary characterization of the regulatory cell population in wild-type mice indicates that the phenotype of the regulatory cell is CD4- CD8-NK1.1+alpha/betaTCR+ or CD4-CD8+NK1.1+alpha/betaTCR+. The hypothesis to be tested is that one or both of these phenotypes is responsible for down-regulation of EAE effector T cells. To test this hypothesis the following Specific Aims are proposed, 1) to assess the role of NK1.1+ alpha/beta+ T cells in recovery from passive EAE using B6 mice with targeted mutations of the immune system, 2) to assess the role of NK1.1+ alpha/beta+ T cells in regulation of self-reactive T cells in the normal individual using B6 mice with targeted mutations of the immune system, 3) to investigate the mechanism of regulation of self-reactive T cells by NK1.1+ alpha/beta+ T cells, 4) to analyze heterogeneity of the a and P-chain CDR3 regions of NK1.1+ alpha/beta+ T cells by spectratypic analysis and nucleotide sequence, and 5) to analyze the interaction of NK1.1+ alpha/beta+ T cells with self-reactive T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030605-24
Application #
6373215
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Ridge, John P
Project Start
1990-05-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
24
Fiscal Year
2001
Total Cost
$253,867
Indirect Cost
Name
Medical College of Wisconsin
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Marty, M C; Alliot, F; Rutin, J et al. (2002) The myelin basic protein gene is expressed in differentiated blood cell lineages and in hemopoietic progenitors. Proc Natl Acad Sci U S A 99:8856-61
Fritz, R B; Zhao, M L (2001) Regulation of experimental autoimmune encephalomyelitis in the C57BL/6J mouse by NK1.1+, DX5+, alpha beta+ T cells. J Immunol 166:4209-15
Fritz, R B; Wang, X; Zhao, M L (2000) The fate of adoptively transferred quiescent encephalitogenic T cells in normal and antigen-tolerized mice. J Neuroimmunol 107:66-72
Fritz, R B; Wang, X; Zhao, M L (2000) Alterations in the spinal cord T cell repertoire during relapsing experimental autoimmune encephalomyelitis. J Immunol 164:6662-8
Lyons, J A; Zhao, M L; Fritz, R B (1999) Pathogenesis of acute passive murine encephalomyelitis II. Th1 phenotype of the inducing population is not sufficient to cause disease. J Neuroimmunol 93:26-36
Lyons, J A; Zhao, M L; Fritz, R B (1998) Pathogenesis of acute passive murine encephalomyelitis I. Importance of host-derived cells as determined by kinetic analysis. J Neuroimmunol 86:92-103
Zhao, M L; Fritz, R B (1998) Acute and relapsing experimental autoimmune encephalomyelitis in IL-4- and alpha/beta T cell-deficient C57BL/6 mice. J Neuroimmunol 87:171-8
Fritz, R B; Russell, J P; Zhao, M L (1998) Persistence of an encephalitogenic T cell clone in the spinal cord during chronic, relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 89:1-9
Fritz, R B; Zhao, M L (1996) Active and passive experimental autoimmune encephalomyelitis in strain 129/J (H-2b) mice. J Neurosci Res 45:471-4
Fritz, R B; Zhao, M L (1996) Thymic expression of myelin basic protein (MBP). Activation of MBP-specific T cells by thymic cells in the absence of exogenous MBP. J Immunol 157:5249-53

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