![]() The spleen plays a major role as a reservoir of monocytes/macrophages and lymphocytes. 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. The spleen is innervated by the splenic nerve (SpN), which consists of an abundant network of interconnecting fibers originating from abdominal ganglia ( 4, 5). 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.Įxtensive 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– 3). Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. 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. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16 +CD14 high pro-inflammatory monocytes. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation 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. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. 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. ![]() Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. 6Non-Clinical Safety, GlaxoSmithKline, Ware, United Kingdom.5Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, United Kingdom.4Department of Surgery, University of Cambridge, Cambridge, United Kingdom.3Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom.2Clinical Science & Services, The Royal Veterinary College, Hatfield, United Kingdom.1Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom.Matteucci 1, Kristina Schlegel 1, Rizwan Bashirullah 1, Dirk Werling 5, Kim Harman 2, Alison Rowles 6, Refet Firat Yazicioglu 1, Jesmond Dalli 3, Daniel J. Fjordbakk 2†, Sebastien Ouchouche 1, Paul B. Sokal 1*‡, Alex McSloy 2‡, Matteo Donegà 1‡, Joseph Kirk 2, Romain A.
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