Multiple sclerosis (MS) is a devastating disease of the central nervous system characterized by loss of the myelin sheath surrounding nerve processes, leading to impaired conduction and permanent disability. Over 400,000 Americans are currently diagnosed with this illness, with another 10,000 added to this number each year. The disease is generally accepted to be the result of a derailed immune system responding to myelin- derived molecules;as such, most therapies for MS focus on controlling this self-reactivity by decreasing immune responses. However, one therapy in particular, glatiramer acetate (Copaxone(R)), is able to ameliorate the symptoms of MS without immunosuppression. Unfortunately, its mechanism has been generally unknown since its discovery almost 40 years ago. Recently, evidence has suggested that CD8+ T cells may be responsible for exerting the therapeutic effects of the drug. In response to treatment with the drug, these cells increased in number, secreted regulatory cytokines, and showed the ability to counter pathogenic cell growth in vitro. Therefore, investigation of these drug-induced regulatory CD8+ T cells is warranted. Rather than focus on drug effects in human patients, it is more useful to study its effects in the mouse model of MS, experimental autoimmune encephalomyelitis, or EAE. Glatiramer acetate was first discovered in the murine model and only later transitioned to human use, suggesting a shared mechanism of action between mouse and man. In the mouse, the drug is shown to be ineffective in mice deficient in CD8+ T cells. Moreover, by transferring drug- induced CD8+ T cells into wild-type and CD8-deficient mice, suppression of clinical disease was evident. Several molecules have already been identified which are necessary for drug action, including immunoregulatory cytokines and molecules involved in cell death. This study aims to further the knowledge of these drug-induced cells by investigating the mechanism by which these cells suppress disease. To do so, the molecules necessary for suppression will be identified, as well as the obligate cell populations that induce and active the regulatory population. The regulatory CD8+ T cells will be characterized in terms of cellular markers as well as secreted factors, and finally, the element of glatiramer acetate that induces this population will be identified. This research will lead directly to the development of more effective therapies for MS as well as other autoimmune diseases while simultaneously expanding the basic knowledge of an understudied area of immunology.

Public Health Relevance

This research will address the mechanism of an FDA-approved therapy for demyelinating disorders of the central nervous system that enjoys widespread use in the United States and globally, leading to improved therapeutics for a host of autoimmune conditions as well as an increased understanding of the basic mechanisms of immune regulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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NST-2 Subcommittee (NST)
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Utz, Ursula
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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