Treatment of chronic inflammatory diseases with implantable medical devices*

Implantable devices are increasingly used in the treatment of diseases which have historically been targeted only with small molecule and biological therapeutic agents. In addition to well-established products such as subcutaneous insulin pumps and intra-arterial chemotherapy pumps, where the implantable device merely serves as a more efficient means of delivering the drug, there are a number of recently developed therapeutic approaches in which the implanted device itself functions to directly treat the underlying medical condition. One particularly successful example of this strategy is cardiac resynchronization using biventricular pacing devices for congestive heart failure (CHF). These devices were approved for marketing after having been proved to prolong survival in patients whose disease had progressed despite medical management.¹ Implantable device products are now approved or in late-stage development for many other traditional “medical” disorders such as hypertension, obesity, diabetes, Parkinson’s disease, and glaucoma. Recent advances in understanding the interplay between the central nervous system and the immune system have made possible a feasible implantable device approach that may similarly find use in the management of rheumatoid arthritis (RA) and other chronic inflammatory diseases.²

NEUROSTIMULATION OF THE CHOLINERGIC ANTIINFLAMMATORY PATHWAY

The vagus nerve mediates an important neural reflex which senses inflammation both peripherally and in the central nervous system, and downregulates the inflammation via efferent neural outflow to the reticuloendothelial system. The efferent arm of this reflex has been termed the “cholinergic antiinflammatory pathway” (CAP). The CAP serves as a physiological regulator of inflammation by responding to environmental injury, pathogens, and other external threats with an appropriate degree of immune system activation.³ An increasing body of evidence indicates that the CAP can also be harnessed to reduce pathological inflammation. Electrical neurostimulation of the vagus nerve (NCAP) in an appropriate manner with an implantable device is emerging as a novel and potentially feasible means of treating diseases characterized by excessive and dysregulated inflammation.

Our current understanding of the CAP began with the observations of Kevin Tracey and colleagues over a decade ago. They demonstrated that systemic, hepatic, and splenic tumor necrosis factor (TNF) production as well as the physiological manifestations of endotoxemic shock in rodents were worsened by vagotomy and ameliorated by electrical stimulation of the cervical vagus nerve (VNS). Further, based on in vitro experiments they postulated that this effect was mediated directly by acetylcholine acting through specific receptors on macrophages in the reticuloendothelial system.⁴ It was later demonstrated that reducing the response to endotoxemia using NCAP required an intact spleen, and selective anatomical lesion experiments showed that an intact neural pathway to the spleen from the cervical vagus through the celiac ganglion and the splenic nerve was also necessary for this effect.⁵ Within the spleen itself, nerve fiber synaptic vesicles are found in close apposition to TNF-secreting macrophages.⁶ The α-7 nicotinic acetylcholine receptor, expressed on the surface of macrophages, is essential for the NCAP effect as demonstrated by antisense oligonucleotide and targeted disruption experiments.⁷ In the macrophage, the α-7 nicotinic acetylcholine receptor does not appear to transduce signals through ion channels, as is the case in neuronal tissue. Rather, the NCAP effect is mediated at the subcellular level by alterations in the NF-κB and JAK/STAT/SOCS pathways.^8,9

When taken together, these studies show that NCAP has a dual set of immunological effects: it reduces production of systemically active cytokines by resident spleen cells and also causes circulating cells which traverse the spleen to develop an altered phenotype with reduced expression of inflammatory mediators and adhesion molecules upon trafficking to inflamed tissue.

An important characteristic of NCAP delivered by VNS is that very brief episodes of stimulation result in a remarkably prolonged biological effect. Huston et al delivered a single 30-second electrical VNS or sham treatment in rats, and then induced endotoxemia with intraperitoneal lipopolysaccharide (LPS) at varying times after VNS. Interestingly, this brief VNS stimulation reduced production of serum TNF in response to systemic LPS exposure for up to 48 hours. Similarly, after only 60 minutes of exposure to acetylcholine, cultured human macrophages are changed in phenotype such that they become refractory to in vitro LPS stimulation for up to 48 hours thereafter.¹⁵ The consistency of this phenomenon across species is corroborated by preliminary data in a canine model where 60-second VNS treatment results in reduced LPS-inducible TNF production in a whole-blood in vitro release assay for several days after the VNS (M Faltys, personal communication). A duration of biological effect lasting hours to days after periods of stimulation lasting for only seconds to minutes implies that an implantable device will probably only need to operate with very short daily duty cycles to effectively elicit an NCAP response. This will in turn greatly reduce the necessary size and complexity of the device itself, and increase its functional lifespan, with resultant reductions in overall cost of the treatment.