Date of Award

3-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Sangeeta S. Chavan, PhD

Second Advisor

Kevin J. Tracey, MD

Abstract

Immunity is an essential function of organisms which allows for homeostasis and survival. A large body of data established the intrinsic regulatory mechanisms of the immune system as residing within the tissues and structures of the reticuloendothelial system. These regulatory systems are enhanced and supplemented by reflex circuits, consisting of discreet connections of neurons to sites of immune responses. The inflammatory reflex is a prototypical neural circuit in which signals arising in the vagus and splenic nerves regulate the production of cytokines by the spleen. Targeting this reflex through the auricular branch of the vagus nerve, we discovered that a non-invasive vibrotactile device therapy inhibits inflammatory cytokine production in healthy subjects, as well as attenuates disease activity in rheumatoid arthritis patients. These findings support a potential therapeutic role of this modality, and suggest the auricular branch of the vagus nerve is a functional component of the inflammatory reflex. While this and other vagus nerve stimulation modalities have been shown to regulate inflammatory responses in pre-clinical models and in pilot clinical trials of human subjects, it is unclear how these responses are specifically modulated by vagus nerve signaling. To investigate this, we studied the role of vagus nerve stimulation parameters on the control of serum cytokines. We discovered that specific patterns of electrical stimulation modulate the levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10), suggesting that vagus-mediated control of inflammation may depend on specific patterns of neural activity. How such circuits might regulate peripheral adaptive and innate immune responses is unclear; to investigate such control mechanisms, we explored the role of neural circuits in the lymphatic trafficking of antigen. We discovered that peripheral neural circuits regulate lymphatic antigen trafficking, and further began a series of unpublished studies to investigate the role of these circuits in the clinically-relevant setting of cancer metastasis.

Download

Share

COinS