Image credit: John Lund | Blend Images. Image courtesy of Getty Images.
Image credit: John Lund | Blend Images. Image courtesy of Getty Images.

The immune system’s inflammatory response is a double-edged sword. Inflammation is a highly complex process which is critical for fighting infections and repairing damaged tissues after injury, but when unregulated, it can result in serious disease. Immune cells and pro-inflammatory effector molecules called cytokines are key mediators of inflammation; together, they combat infectious agents through various processes. A characteristic feature of these processes is fever, which creates an optimal environment for immune cells to act against viruses and bacteria. Uncontrolled or excessive inflammation is detrimental to the host, as it causes damage to the host’s cells and tissues. Therefore, the immune system has a system of checks and balances to regulate inflammation, which is a process called immune homeostasis. If homeostasis breaks down, inflammation is prolonged and healthy tissue is destroyed, resulting in autoimmune disease. Immune homeostasis was long thought to be self-regulated, but research into the intersection of the nervous and immune systems has revealed a neural regulatory component in immune homeostasis. This is paving the way for the development of breakthrough bioelectronic medicines targeting neural activity to prevent excessive inflammation and treat autoimmunity.

Early work from the 1990s demonstrated that disrupting the vagus nerve, which is one of the largest nerves in the body, negatively impacted immune homeostasis.[pullquote]When researchers severed the vagus nerve in mice, not only did the mice lose regulatory control of the cardiovascular system, they also lost their fever response to pro-inflammatory cytokines.[/pullquote]The vagus nerve originates in the brain stem, innervates multiple organs in the abdomen, and regulates several physiological functions. When researchers severed the vagus nerve in mice, not only did the mice lose regulatory control of the cardiovascular system, they also lost their fever response to pro-inflammatory cytokines. The pivotal discovery that there is neural control of the inflammatory immune responses laid the groundwork for the description of the inflammatory reflex arc, the neural circuit that regulates inflammation upon injury or infection.

The inflammatory reflex arc maintains homeostasis by suppressing the innate immune system, the body’s first response against harmful stimuli. Damaged or infected cells secrete pro-inflammatory cytokines such as tumour necrosis factor (TNF), which initiates inflammation and also sends a neural signal to the brain stem. The brain stem responds to this communication via the vagus nerve, which signals to the spleen, a major immunological site. This results in the release of neural signaling molecules, i.e. neurotransmitters, which can act on innate immune cells such as macrophages to decrease production of TNF. The innate immune system is subsequently regulated in a fast and specific manner in order to prevent excessive inflammation.

Abnormal vagus nerve activity is characteristic of a number of autoimmune diseases, and researchers quickly delved into elucidating the role of the inflammatory reflex in autoimmunity. Dr. Kevin J. Tracey, President and CEO of the Feinstein Institute for Medical Research, is a leader in this field, having first described the inflammatory reflex. Tracey’s research group studies the modulation of the inflammatory reflex in rheumatoid arthritis (RA). They demonstrated that severing the vagus nerve in mice could exacerbate arthritis, while stimulation of vagus signalling could ameliorate disease. These promising results opened the door for new potential RA therapies in humans. Tracey co-founded SetPoint Medical, a start-up specializing in bioelectronics, and in 2011, the first clinical trial of bioelectronic modulation of the vagus nerve for RA therapy commenced. Using a neuromodulator previously approved for use in epilepsy, eight patients were implanted with the device in their neck along the vagus nerve. The device was then programmed to stimulate vagus nerve activity in attempt to suppress inflammation. Vagus nerve stimulation in all patients showed a decrease in disease symptoms after 6 weeks, with two patients going into disease remission. So far, no severe side effects of the therapy have been reported.

SetPoint Medical’s neuromodulator will be dime-sized, and users will use software on smartphones or tablets to charge and reprogram the device. While this raises concern about external parties hacking the device’s software, many RA patients are excited for this new specific and directional therapy and were eager to participate in the first clinical trial. SetPoint Medical is already advertising its innovative therapy for a variety of autoimmune diseases from RA to Crohn’s Disease. The potential of research into neural immunoregulation promises to be exciting, but despite this enthusiasm, continued assessment of the safety and efficacy of bioelectronic therapies to treat autoimmune disease, especially regarding long-term effects, still needs to be conducted.

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