Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CMS) and is responsible for long-term morbidity in 250,000-350,000 people in the United States. Although the precise etiology of MS is unknown, it is thought to be a T-cell-mediated process due to characteristic histologic features and the presence of neuroantigen-specific immune responses in the blood and cerebrospinal fluid. Thus, several immunomodulatory therapies are being investigated to combat this disease. The vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses. Although both diseases are thought to be mediated and regulated by CD4+ T cells, several reports from others and us present strong evidence for a role of CD8+ T cells in the pathogenesis. However, the functional relevance of autoreactive CNS-targeted CD8+ T cells remains a poorly studied aspect of MS immunopathology. Using novel immunophenotypic approaches, we have recently shown that CNS-specific autoreactive CD8+ T cell responses are far more prevalent in MS patients than appreciated thus far. Moreover, they exhibit a functional phenotype that suggests a mixed functional profile and appears distinct from autoreactive CD8+ responses in healthy subjects. We thus hypothesize that CNS-specific autoreactive CD8+ T cells play an important role in the pathogenesis and intrinsic immune modulation of MS. Through studies proposed in this application, we will evaluate the role of CNS-specific CD8+ T cells by delineating their phenotypic and functional features, their fine specificity and their activation requirements. We believe that understanding the biology of this critical aspect of the underlying immune response will provide important insights that can be utilized for therapeutic benefit in MS and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065463-04
Application #
7826792
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2007-05-10
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$372,812
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Sinha, Sushmita; Crawford, Michael P; Ortega, Sterling B et al. (2015) Multiparameter Flow Cytometric Assays to Quantify Effector and Regulatory T-Cell Function in Multiple Sclerosis. J Mult Scler (Foster City) 2:
Sinha, Sushmita; Boyden, Alexander W; Itani, Farah R et al. (2015) CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis. Front Immunol 6:619
Ortega, Sterling B; Kashi, Venkatesh P; Cunnusamy, Khrishen et al. (2015) Autoregulatory CD8 T cells depend on cognate antigen recognition and CD4/CD8 myelin determinants. Neurol Neuroimmunol Neuroinflamm 2:e170
Cunnusamy, Khrishen; Baughman, Ethan J; Franco, Jorge et al. (2014) Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells. Clin Immunol 152:115-26
Sinha, Sushmita; Itani, Farah R; Karandikar, Nitin J (2014) Immune regulation of multiple sclerosis by CD8+ T cells. Immunol Res 59:254-65
Ortega, Sterling B; Kashi, Venkatesh P; Tyler, Andrew F et al. (2013) The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis. J Immunol 191:117-26
Ayers, Chris L; Mendoza, Jason P; Sinha, Sushmita et al. (2013) Modulation of immune function occurs within hours of therapy initiation for multiple sclerosis. Clin Immunol 147:105-19
Biegler, Brian W; Yan, Shirley X; Ortega, Sterling B et al. (2011) Clonal composition of neuroantigen-specific CD8+ and CD4+ T-cells in multiple sclerosis. J Neuroimmunol 234:131-40
Baughman, Ethan J; Mendoza, Jason P; Ortega, Sterling B et al. (2011) Neuroantigen-specific CD8+ regulatory T-cell function is deficient during acute exacerbation of multiple sclerosis. J Autoimmun 36:115-24
York, Nathan R; Mendoza, Jason P; Ortega, Sterling B et al. (2010) Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis. J Autoimmun 35:33-44