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Publication Date

2012-11-14

Availability

UM campus only

Embargo Period

2012-11-14

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2012-10-30

First Committee Member

John R. Bethea

Second Committee Member

Thomas R. Malek

Third Committee Member

Zhibin Chen

Fourth Committee Member

Abigail S. Hackam

Fifth Committee Member

Norma Sue Kenyon

Sixth Committee Member

Alberto Pugliese

Abstract

Multiple Sclerosis (MS) is a debilitating autoimmune disease whose pathological hallmarks are intermittent demyelination, axonal damage, and inflammation throughout the central nervous system (CNS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS, we have analyzed how interleukin-7 receptor alpha (IL7Ra), nuclear factor-kappa B (NF-κB), and tumor necrosis factor (TNF) individually contribute to this immune response. We show that limiting IL7Ra expression to thymic tissue results in a less severe form of the disease as seen by reduced paralysis, myelin damage, and inflammation. This correlated with dampened T cell effector responses, namely decreased TNF production. Chimeric mice generated by bone marrow transplant, which limited expression of IL7Ra to cells of either hematopoietic or non-hematopoietic origin, developed severe EAE. Only mice that lack IL7Ra throughout both compartments are dramatically protected from disease, suggesting that IL7Ra expression in multiple cell types contributes to EAE. IL7Ra can be induced by the transcription factor NF-κB, which regulates genes involved in inflammation, a process that astrocytes help to coordinate within the CNS. Mice with astroglial inhibition of NF-κB developed a reduced EAE phenotype with significantly less immune infiltration and dampened T cell function. As dramatic reductions in TNF were seen after inhibition of either IL7Ra or NF-κB, we went on to compare TNF inhibitors and found that specifically blocking the soluble from of TNF is beneficial in EAE. Therefore IL7Ra, NF-κB, and TNF signaling pathways contribute to the detrimental aspects of EAE, and each serves as an optimal target in developing MS therapies.

Keywords

experimental autoimmune encephalomyelitis; interleukin-7 receptor alpha; nuclear factor-kappa B; tumor necrosis factor; Multiple Sclerosis; T cell

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