Inflammatory peripheral neuropathies are a considerable social and economic burden to our Veterans and to the Veterans Health Administration. Encompassing both known infectious or possibly infectious etiologies, inflammatory neuropathies constitute one of the largest and least understood spectrums of neurologic disorders. Inclusive among these disorders is acute inflammatory demyelinating polyradiculopathy (AIDP), a highly disabling inflammatory autoimmune disease of the peripheral nervous system that is characterized by acute/subacute symmetrical paresis with are flexia progressing to neuromuscular paralysis. Despite its overwhelming prevalence and socioeconomic impact, the treatment of Veterans with inflammatory peripheral neuropathies, including AIDP, remains palliative and largely relies on the use of non-specific immune- modulating therapies. Cytokine-mediated recruitment and trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves is a well-established early pathological hallmark of inflammatory peripheral neuropathies, including AIDP. A strong correlation between elevated plasma concentrations of TNF-? and clinical severity of AIDP has been described. The mechanism by which TNF-? contributes to peripheral nerve injury in AIDP remains, however, unclear. Localized GTPase-dependent activation of the peripheral nerve vascular endothelium in response to proinflammatory cytokines may represent an initiating pathological insult. In this two-year VA RR&D supported CDA-1 application, we hypothesize that trafficking of autoreactive leukocytes across the blood-nerve barrier in AIDP occurs, in part, by a mechanism that involves TNF-? mediated monomeric GTPase-dependent expression of MCP-1 and ICAM-1. This hypothesis will be tested in vivo utilizing an established clinically-translatable rat model of AIDP (experimental autoimmune neuritis, EAN) and in vitro with cultured peripheral nerve microvascular endoneurial endothelial cells (PNMECs). In Objective 1, we will determine the mechanistic role of monomeric GTPases on activation of the blood-nerve barrier in vivo by quantifying the effects of prenyltransferase inhibitors on (a) the clinical severity and course of EAN, (b) EAN-induced changes in peripheral nerve function and on (c) the content and distribution of inflammatory mediators (TNF-?, MCP-1, ICAM-1) and immune infiltrates (macrophages and leukocytes) within sciatic nerves of EAN-affected rats compared with vehicle-treated controls. In Objective 2, we will determine the mechanistic role of monomeric GTPases on TNF-? mediated activation of PNMECs in vitro by quantifying the dose- and time-dependent effects of prenyltransferase inhibitors on relative changes in TNF-? mediated (a) expression and secretion of MCP-1 and (b) expression of ICAM-1. If time permits, we will further identify in this Objective the monomeric GTPases involved in TNF-? mediated MCP-1 and ICAM-1 expression using available dominant-negative GTPase mutants. The goal of this program is to significantly advance the development of novel, selective immune-modulating strategies for the management and rehabilitation of Veterans with debilitating inflammatory peripheral neuropathies, while providing a productive and enriching training environment for the development of a young VA neuroscientist.
Inflammatory peripheral neuropathies remain a considerable social and economic burden to our Veteran patient population and to the Veterans Health Administration. In many cases, acquired forms of inflammatory neuropathies exhibit a pathogenic autoimmune etiology of unclear origin. Emerging evidence strongly implicates aberrant trafficking of autoreactive leukocytes as an initial pathological insult. Despite a considerable social and economic impact, the rehabilitative management of Veterans with acquired autoimmune neuropathies remains palliative and awaits the development of novel selective immune-modulating therapies. With this two-year CDA-1 training program, mechanisms governing the trafficking of autoreactive leukocytes across the blood-nerve barrier will be specifically elucidated using a combined in vivo and in vitro integrated experimental approach utilizing an established, clinically-translatable rat model of acquired autoimmune inflammatory neuropathy and microvascular endothelial cells harvested and purified from rat peripheral nerve.