Mechanistic Role of Monomeric GTPases in Experimental Autoimmune Neuritis

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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.