Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in over 300,000 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 assessing the immune system in MS have focused on evaluating and targeting CD4+ T cell responses. However, several reports from others and us present strong evidence for a role of CD8+ T cells in the pathogenesis and immune regulation of MS. Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDA-approved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. We have provided the first direct evidence that Copaxone induces not only CD4+, but also CD8+ T cell responses. Copaxone-specific CD8+ T cell responses are deficient in untreated MS patients and are restored during Copaxone therapy. We have thus uncovered a novel mechanism through which this FDA- approved drug may mediate its immunologic effects. We hypothesize that Copaxone-induced CD8+ T cells are important regulatory populations of cells that mediate the clinical effects of the drug through multiple mechanisms. In this project, we will continue to delineate the functional role and diversity of these suppressor CD8+ T cells and dissect the requirements of appropriate presentation of Copaxone to induce their response. We believe these studies will provide important insights into an overlooked area of MS immunology and will help generate better immunotherapeutic strategies.

Public Health Relevance

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system (CNS). Glatiramer acetate (GA, Copaxone) is an immune modulatory agent that is FDA-approved for the treatment of RRMS. However, the mechanism of its action still remains poorly understood. While prior studies in MS immunology have focused on CD4+ T cells, we have provided the first direct evidence that Copaxone induces not only CD4+, but also CD8+ T cell responses. These cells may play a very important role not only in mediating the effect of this drug but also as important regulators of the healthy immune system. In this project, we will continue to delineate the functional role and diversity of these suppressor CD8+ T cells. We believe these studies will provide important insights into an overlooked area of MS immunology and will help generate better immunotherapeutic strategies in the future. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI053439-05A2
Application #
7465102
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2003-07-01
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2008
Total Cost
$104,667
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
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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
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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

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