Publication Date

2014-01-17

Availability

Embargoed

Embargo Period

2015-01-17

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2013-12-12

First Committee Member

John R. Bethea

Second Committee Member

Helen M. Bramlett

Third Committee Member

Samita S. Andreansky

Fourth Committee Member

Robert W. Keane

Fifth Committee Member

Jae K. Lee

Sixth Committee Member

Richard L. Riley

Seventh Committee Member

Thomas E. Lane

Abstract

Patients with chronic spinal cord injury (SCI) are at higher risk than the general population of developing infections and their prognosis is often much poorer. The disruption of the normal balance between central nervous system and immune system following SCI induces immunodepression, leading to a compromised capacity to combat infections such as influenza virus in patients with SCI. Using a contusion model of SCI at thoracic level 9, we analyzed the chronic effect of SCI on the peripheral immune system in mice, with a focus on T-cell immunity. We found that although the splenic T-cell number was not changed during chronic SCI, their function as measured in cytokine production, upon ex vivo stimulation, was diminished. We further explored the mechanisms of SCI-induced T-cell dysfunction and demonstrated that chronic SCI increased sympathetic nervous system (SNS) activity and elevated norepinephrine level in the spleen. Higher splenic norepinephrine level correlates with a T-cell exhaustion phenotype as shown by higher expression of exhaustion marker PD-1 on T-cells. Up-regulated PD-1 expression contributes to the CD8+ T-cell functional deficiency in chronic SCI mice, as blocking PD-1 signaling in vitro restored the CD8+ T-cell function. We next investigated how chronic SCI affects the antiviral immunity in mice using a well-established influenza virus mouse model. Virus specific immunity was analyzed in chronically injured mice at different times post-infection in comparison to uninjured controls. The data indicates that chronic SCI injury impairs the ability of the animals to mount an antiviral immunity. While all the control mice cleared the virus from the lungs 10 days post-infection, significant number of SCI mice did not clear the virus. This was attributed to severe deficit in both virus-specific antibody and CD8+ T-cell response in injured mice. Taken together, our study indicates that the alteration of sympathetic activity following chronic SCI induces T-cell exhaustion, which in turn impairs T-cell function and contributes to immune depression. Moreover, we demonstrate that the antiviral immunity against influenza virus infection is compromised in mice with chronic SCI. Our results highlight the important role of central nervous system and neurotransmitters in regulation of immune cell function. Our study also suggests that blockade of PD-1 pathway is a potential therapeutic strategy to restore immunity in patients with chronic SCI.

Keywords

spinal cord injury; T-cell exhaustion; PD-1; norepinephrine; influenza

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