Chronic inflammatory demyelinating polyneuropathy (CIDP) is considered the peripheral counterpart of multiple sclerosis because of some similarities in their immunopathogenesis and course of illness. The B7/CD28:CTLA-4 costimulatory pathway plays an important role in the regulation of immune responses in both diseases. Elimination of B7-2 in the nonobese diabetic (NOD) mouse prevents the development of diabetes, but leads to the development of a spontaneous autoimmune neuropathy mimicking CIDP (Salomon et al., 2001). This unique model provides an opportunity to study the role of novel therapeutic targets in inflammatory neuropathies. Examples of these targets for anti-autoimmune intervention include the so called sphingosine 1-phosphate (S1P) receptors that are expressed by lymphocytes, endothelial cells and Schwann cells. S1P receptors are implicated in the regulation of lymphocyte trafficking (Brinkmann et al., 2002; Mandala et al., 2002). The goal of this proposal is to investigate whether drugs that act on S1P receptors can ameliorate the disease severity in B7-2 deficient NOD mice when administered after the onset of symptoms. Clinical, electrophysiological and histological assessments will be carried out. To examine whether the function of effector cells is modulated by test agents, immunohistochemical studies will be performed on nerve sections, focusing on cytokine secretion and expression of inducible nitric oxide synthase (iNOS). The effect of test agents on the integrity of blood nerve barrier will be investigated. In addition, we will examine whether S1P signaling in Schwann cells influence their susceptibility to proinflammatory cytokines, or play a role in Schwann cell differentiation and myelination. These studies will tell us whether drugs that target S1P receptors have a therapeutic role in CIDP or other inflammatory neuropathies, provide insights into the pathogenesis of spontaneous autoimmune polyneuropathy in our model, and elucidate the function of S1P receptors in Schwann cells- the target of immune attack in CIDP.

R21NS049014

2005-04-01

2008-03-31