Multiple sclerosis (MS) is a devastating, demyelinating disease of the central nervous system (CNS) and is the leading cause of neurological disability in young adults. Self-reactive myelin-specific T cells are believed to initiate MS and to play a prominent pathogenic role throughout the course of disease. Developing therapies for MS has been challenging, in part because the heterogeneity seen in inflammatory infiltrates, lesions and clinical course suggest that the relative contribution of specific pathogenic mechanisms may vary among individual patients. This heterogeneity may reflect individual variation in the types of effector cells recruited to the CNS that induce tissue damage via distinct mechanisms. An additional level of complexity arises from the fact that the inflammatory milieu within the tissue is dynamic and will reflect the relative abundance of specific T cells subsets with different activities. Thus, a better understanding of how the activit of distinct T cell subsets in the same microenvironment influence each other and how their interactions with CNS resident cells act in concert to promulgate inflammation and induce tissue damage, is essential to develop effective therapeutic intervention. The role of CD4+ myelin-specific T cells has been extensively studied in MS and the animal model experimental autoimmune encephalomyelitis (EAE). Two CD4+ effector T cell subsets, IFN-?- producing Th1 cells and IL-17-producing Th17 cells, have been implicated in the pathogenesis of MS, and these subsets induce different inflammatory patterns within the central nervous system (CNS) in EAE. The role of CD8+ myelin-specific T cells has not been well-studied, even though a large body of data implicates a role for CD8+ T cells in MS. Few models have been developed to study the role of CD8+ T cells in MS, therefore little is known about how this T cell subset influences the disease process. This application proposes to use newly developed tools to investigate the mechanisms by which CD8+ myelin-specific T cells influence EAE initiated by CD4+ T cells. Our fundamental hypothesis is that myelin-specific CD8+ T cells are recruited to the CNS during disease initiated by CD4+ T cells, and that the simultaneous, but distinct, activities of CD4+ and CD8+ T cells determine the pattern of lesion formation, tissue damage and clinical signs.
Three aims are proposed to test this hypothesis: 1. DETERMINE HOW RECRUITMENT OF MYELIN-SPECIFIC CD8+ T CELLS MODIFIES THE COURSE OF ACUTE AND CHRONIC EAE INDUCED BY CD4+ T CELLS. 2: DEFINE THE EFFECTOR FUNCTIONS ACQUIRED BY CD8+ T CELLS RECRUITED TO THE CNS DURING CD4 T CELL-INITIATED EAE. 3: DETERMINE THE INFLUENCE OF MYELIN-SPECIFIC CD8+ T CELLS ON CNS AUTOIMMUNITY INDUCED BY TH1 VERSUS TH17 CELLS.

Public Health Relevance

To generate more effective therapies to treat multiple sclerosis, an autoimmune disease in which both CD4 and CD8 T cells contribute, it is important to understand the role of both T cell subsets. We will study how CD8 T cells modulate the activity of CD4 T cells in experimental autoimmune encephalomyelitis, an animal model of MS. Our studies will help understand the variable effects of current therapies as well as develop new therapeutic strategies that better address the disease exhibited by individual patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
1R37AI107494-01
Application #
8561026
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2013-06-10
Project End
2018-05-31
Budget Start
2013-06-10
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$452,747
Indirect Cost
$192,423
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195