Publication Date

2012-07-31

Availability

Open access

Embargo Period

2012-07-31

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2012-07-23

First Committee Member

Eckhard R. Podack

Second Committee Member

Rebecca Adkins

Third Committee Member

John Bethea

Fourth Committee Member

Gregory E. Conner

Fifth Committee Member

Tom Malek

Sixth Committee Member

Omid Akbari

Abstract

Chronic allergic lung inflammation results in airway remodeling and permanent structural changes. Here we show that administration of agonists to TNF receptor super family 25 (TNFRSF25) in vivo causes expansion of natural and allergen-specific CD4+FoxP3+ regulatory T-cells (Tregs), which can prevent allergic lung immunopathology in the acute setting, and if administered during chronic allergic lung inflammation, inhibits inflammation and reverses airway remodeling. TNFRSF25-expanded Tregs reduced eosinophilia in the bronchoalveolar lavage fluid, reduced expression of T-helper type-2 (Th2) cytokines and blunted allergen-specific Th2 effector responses. Previously established chronic airway remodeling, as measured by goblet cell hyperplasia and subepithelial collagen deposition, was reversed in mice treated with TNFRSF25-agonists but not in controls. The results indicate that in vivo Treg expansion by TNFRSF25 agonists, during chronic lung inflammation leads to durable suppression of inflammation and reversal of airway remodeling, which may be a result of shifting the antigen-specific T-cell population toward a regulatory response.

Keywords

Allergic Asthma; T-regulatory Cells; TNFRSF25; TL1A; Immunotherapy

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