Combining Immune Regulation and Myelin Repair for Treatment of Relapsing EAE

MS is a complex autoimmune disease whereby cells of the immune system initiate an immune-mediated attack against myelin in the brain that supports neuronal conduction. The initiating causes of MS are not fully understood, and evidence suggests there are likely multiple causes. The absence of a single therapeutic target has made design of treatment strategies difficult. Currently FDA approved drugs for the reduction of frequency and severity of disease relapses in MS patients, such as corticosteroids, IFNb-1B (BetaseronÒ), IFN-b1A (AvonexÒ), Copaxone (Glatiramer Acetate) Tysabri and Gilenia, have only limited efficacy in a subset of MS patients and are associated with multiple serious side effects. These therapeutics all possess mechanisms which act via a non-specific decrease in T cell activation and/or function, or via blockade of the ability of inflammatory cells to enter the CNS thus indirectly allowing for limited endogenous repair processes. We have recently demonstrated two effective means of ameliorating disease in a mouse model of MS: a short-course of administration of anti-CD80 Fab antibody or tolerance induction using biodegradable PLG nanoparticles encapsulating myelin antigens (Ag-PLG). Although mice treated with either of these immune regulatory strategies fail to display disease relapses, they retain significant clinical deficits presumably due to failure to repair myelin destroyed during the acute attack. Here we propose to test the effects of treatment with our immunoregulatory strategies combined with guanabenz, an FDA-approved drug for high blood pressure, which shows potent myelin protective/stimulating effects in in vitro culture studies. In addition to combining guanabenz treatment with administration of anti-CD80 Fab, we want to assess this treatment in combination with tolerance induced by myelin Ag-PLG nanoparticles which we have recently published (Nature Biotechnology 30:1217, 2012) to induce profound, long-lasting tolerance effective for both the prevention and treatment of disease in the R-EAE mouse model of MS. This work will lend important information relevant to the eventual combined use of immunoregulation and myelin restorative approaches for the treatment of MS.