Abstract
Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.
Highlights
Extensive evidence exists demonstrating that the efferent arm of the “inflammatory reflex” controls systemic immune responses via neural circuits that target lymphoid organs, in particular the spleen [1,2,3]
Stimulation parameters were initially refined by measuring evoked compound action potentials and physiological parameters during SpN stimulation (SpNS) in terminally-anesthetized pigs
There was a frequency-dependent effect of stimulation on splenic nerve (SpN) conduction velocity and evoked compound action potentials (eCAP) amplitude
Summary
Extensive evidence exists demonstrating that the efferent arm of the “inflammatory reflex” controls systemic immune responses via neural circuits that target lymphoid organs, in particular the spleen [1,2,3]. The spleen is innervated by the splenic nerve (SpN), which consists of an abundant network of interconnecting fibers originating from abdominal ganglia [4, 5] This neuronal plexus runs along the splenic artery (SpA), together forming a neurovascular bundle (NVB), until it enters the splenic parenchyma where it releases neurotransmitters, in particular catecholamines, which subsequently modulate immune cells. This immunomodulatory effect has typically been demonstrated as a reduction in cytokine responses, tumor necrosis factor alpha (TNF-a) [2, 8, 11] This effect has been shown to be dependent on the SpN, and on noradrenaline (NA) released from nerve terminals onto splenic leukocytes [8, 11]. When compared to small animals, the use of large animal models is more appropriate to answer questions on human-relevant clinical device design and therapy translation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
