Doctoral Dissertations

Date of Award

8-2000

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Microbiology

Major Professor

Habib Zaghouani

Committee Members

Robert Moore, Nicholas Potter, Barry Rouse

Abstract

Multiple sclerosis is an inflammatory disease that leads to a demyelination of the CNS that is responsible for the symptomatic neurological deficits, including paralysis. A predominance of evidence supports the idea that this autoimmune disease is mediated through CD4+ T cells reactive to myelin antigens, and as such, these T cells have been shown to be at higher levels in MS patients than in healthy individuals. Likewise, work on Experimental Allergic Encephalomyelitis, an animal model for human MS, has shown that immunization with myelin proteins or transfer of activated CD4+ T cells reactive against myelin antigens are sufficient to transfer disease to naive animals. Therefore this study explores three distinct approaches to target and silence autoreactive T cells within the EAE model of autoimmune disease. Part II investigates the introduction of efficient peptide antagonist ligands to downregulate autoreactive T cells. Part III delves into the consequences of efficient transfer and presentation of self-antigen and altered self-antigen into the fetal thymus and periphery on subsequent autoimmunity and T cell development. Lastly, Part IV explores the outcome of efficient peripheral self-peptide presentation, without induction of co-stimulation thus mimicking peripheral tolerance, and the triggering of anti-inflammatory cytokines to possibly induce anergy of self-reactive T cells and modulate clinically evident autoimmune disease. Each aspect of these studies uses novel Ig-chimeric molecules, which express either self or altered self ligands within the CDR3 region of the heavy chain. These molecules allow for the efficient presentation of the myelin based ligands to T cells and can also induce the production of anti-inflammatory cytokines. The results indicate that in order for antagonist ligands to down regulate a protein based autoimmune response, which would occur during natural disease, the antagonists must be presented efficiently. Furthermore this study demonstrates that introduction of self but not altered self ligands, within the fetal thymus, alleviates subsequent autoimmunity to that self-epitope in later life. Lastly the results reported herein show that treatment of clinically evident autoimmunity, even involving multiple myelin epitopes, is possible by administering aggregated Ig-myelin chimeras into the periphery during the course of disease.

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