Evan B. Stubbs - US grants

DESCRIPTION (provided by applicant): Acute inflammatory demyelinating polyradiculopathy (AIDP) is a common North American and European form of Guillain-Barre'Syndrome (GBS), a disabling inflammatory autoimmune disease of the peripheral nervous system that is characterized by rapid-onset symmetrical paresis with areflexia progressing to neuromuscular paralysis. Considered the leading cause of acute flaccid paralysis in Western countries, GBS occurs with an incidence rate of 0.2-4.0 cases per 100,000. Despite its considerable social impact and economic consequences, studies addressing clinical strategies for the treatment of GBS remain poorly represented. Enhanced infiltration of inflammatory cells into peripheral nerves of GBS patients is strongly suggestive of an immune-mediated pathogenic process. Cellular immunity directed against specific constituents of the peripheral nerve myelin sheath is considered causal in AIDP. The treatment of AIDP/GBS is currently palliative and utilizes non-specific immune-modulating therapies. Advancement of care for GBS patients awaits the development of selective immune-modulating agents or the novel application of existing therapeutic strategies. To address this concern, we recently reported on the application of statins, a group of potent 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, as a novel strategy for the management of experimental autoimmune neuritis (EAN), a well-defined animal model of acute inflammatory peripheral nerve disease. We found that a short-term application of lovastatin was non-toxic and protected against EAN-induced peripheral nerve injury by inhibiting the transendothelial migration of autoreactive leukocytes. How statins affect the migration of autoreactive leukocytes is unclear. In this application, we hypothesize that statins protect against the development of EAN by inhibiting Rho GTPase dependent expression of key cell adhesion molecules on peripheral nerve endothelial cells. We will test this hypothesis using the following Specific Aims: We will determine (1) the dose- and time-dependent effect of lovastatin and simvastatin treatment on Rho-GTPase dependent expression of E-selectin, ICAM-1 and VCAM-1 in primary cultures of rat sciatic nerve endothelial cells and (2) the effect of lovastatin and simvastatin treatment on cell-specific expression of E-selectin, ICAM-1 and VCAM-1 in sciatic nerves harvested from vehicle- or statin-treated Lewis rats with EAN. The overall goal of this application is to define the mechanism by which statins protect against the development of autoimmune inflammatory demyelinating polyradiculopathy. We argue that findings from this study will significantly advance the development of statins as a selective immune-modulating strategy for the treatment of those individuals affected by GBS and related debilitating inflammatory peripheral nerve diseases. PUBLIC HEALTH RELEVANCE Guillain-Barre'Syndrome (GBS) is a potentially highly disabling acquired inflammatory autoimmune disease of the peripheral nervous system that is characterized by a rapid-onset of muscle weakness that in some patients progresses to respiratory failure and paralysis. Subsequent to the virtual eradication of poliomyelitis, GBS is now considered the leading cause of acute flaccid paralysis in Western countries (1) with a reported annual stable incidence rate of 0.2-4.0 cases per 100,000 (2;3), a rate that is surprisingly similar to that reported for multiple sclerosis (1;4). In the US, nearly 10,000 GBS cases are reported annually with an overall yearly social and economic burden exceeding $1.8 billion (5). Despite its considerable social impact and economic consequences, studies addressing clinical strategies for the treatment of GBS remain poorly represented. The overall goal of this application is to define the mechanism by which statins protect against the development of autoimmune inflammatory demyelinating polyradiculopathy. We argue that findings from this study will significantly advance the development of statins as a selective immune-modulating strategy for the treatment of those individuals affected by GBS and related debilitating inflammatory peripheral nerve diseases.

DESCRIPTION (provided by applicant): Inflammatory peripheral neuropathies represent a considerable social and economic burden in the US and worldwide. 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 symmetrical paresis with areflexia progressing to neuromuscular paralysis. Despite its overwhelming prevalence and socioeconomic impact, the treatment of patients with inflammatory peripheral neuropathies, including AIDP, remains palliative and largely relies on the use of non-specific immune-modulating therapies. TNF-¿ mediated recruitment and trafficking of autoreactive leukocytes across the blood-nerve barrier (BNB) and into peripheral nerves is a well-established early pathological hallmark of inflammatory peripheral neuropathies, including AIDP. The chemokine MCP-1 has been identified as a key initiator of this inflammatory cascade and elevated levels of MCP-1 have been detected in plasma and sural nerve of affected patients. Mechanistic studies from our lab have recently demonstrated that release of MCP-1 from peripheral nerve microvascular endoneurial endothelial cells (PNMECs) of the BNB requires the presence of active monomeric GTPases, in particular Cdc42. Hypothesis: Therapeutic administration of geranylgeranyltransferase inhibitor-I will attenuate the development and progression of experimental autoimmune neuritis by inhibiting TNF-¿ mediated Cdc42-dependent release of MCP-1 from peripheral nerve microvascular endoneurial endothelial cells. This hypothesis will be tested in vivo utilizing experimental autoimmune neuritis (EAN), an established clinically-translatable rat model of AIDP and in vitro using primary and transformed cultures of PNMECs. In Specific Aim 1, we will determine the therapeutic potential of prenyltransferase inhibitors on activation of the BNB by assessing (a) the clinical severity and course of EAN (b) EAN-induced changes in peripheral nerve function and (c) the content and distribution of immune infiltrates (macrophages and leukocytes) and MCP-1 in sciatic nerves of EAN rats, compared with vehicle-treated EAN control rats. In Specific Aim 2, we will identify, in vitro, the specific monomeric GTPases involved in the (a) intracellular distribution and (b) release of MCP-1 from TNF-¿ treated PNMECs using targeted siRNA knockdown of individual GTPases. The goal of this two-year exploratory proposal is to determine the therapeutic potential of prenyltransferase inhibitors as novel treatment options for patients with AIDP while continuing to elucidate the mechanisms by which monomeric GTPases promote TNF-¿ mediated inflammatory activation of the blood-nerve barrier.