Date of Award

1-1-2013

Embargo Period

1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Narendra L. Banik

Second Advisor

Craig Beeson

Third Advisor

Azizul Haque

Fourth Advisor

Baerbel Rohrer

Fifth Advisor

Tamara Nowling

Abstract

Multiple sclerosis (MS) is a complex demyelinating CNS disease that involves both immunologic and neurodegenerative mechanisms of pathophysiology. MS is characterized by lymphocyte infiltration in the CNS resulting in extensive axonal neurodegenerative processes. The current therapies for MS act through either immunomodulatory or immunosuppressive mechanisms; none address both the immune and degenerative arms of the disease. The immunomodulatory agents are generally broad spectrum and non-specific immunosuppression and are associated with significant toxicities. Thus, novel therapies or therapeutic strategies are needed to fully combat both inflammatory and neurodegenerative events that define MS. The animal model experimental autoimmune encephalomyelitis (EAE) is used to study MS and exhibits both inflammatory and neurodegenerative arms of the disease. The overall hypothesis of the study is to evaluate two independent but complementary therapeutics for their effect on the two pronged disease and as a combination synergistic therapy. Calpain is upregulated in EAE CNS tissue, and its activity correlates with neurodegeneration. Further, inhibitors of calpain decrease EAE disease signs by reducing inflammatory and neurodegenerative events. Calpain released from activated T cells degrades myelin basic protein (MBP); calpain inhibitor treatment lessens this neurodegenerative arm of the disease. Another treatment shown to decrease disease severity in EAE rodents is the use of altered peptide ligands (APLs) that mimic myelin-derived autoantigens to cause a shift away from pro-inflammatory cytokine production while up-regulating the Tregs. APLs with a nitrogen substitution in the a-carbon in an amino acid results in an aza-peptide that has higher biological stability than traditional peptide-based APLs. The current study shows that calpain inhibitor SNJ1945 diminishes disease in vivo, diminishes inflammation in the periphery and shows neuroprotection in the CNS. Aza-APL, 3aza, treatment shows a significant reduction in disease in vivo as well as a switch to Treg subset from inflammatory T cell types in the periphery. Combined the treatments show further reduction in disease, inflammation and neurodegeneration than either alone. The study supports combination therapy as the future for MS as well as focusing on the two arm problem of the disease.

Comments

Pages 40 and 41 repeat after page []. Page numbers 114-116 skipped by author.

Rights

All rights reserved. All rights reserved. Copyright is held by the author.

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