Combining Immune Tolerance and Myelin Repair Therapy in T cell-driven MS Models

Project: Research project

Project Details

Description

Multiple Sclerosis (MS) is an autoimmune disease of the CNS characterized by demyelination and
neurodegeneration in response to perivascular T cell and mononuclear cell infiltration. Currently FDA-approved
MS disease modifying therapies are global immunosuppressants mediating non-specific inhibition of T cell
activation/function and/or trafficking. These drugs generally have limited efficacy and/or are associated with
serious side effects. The Miller lab has recently demonstrated an effective means of ameliorating disease in
the EAE mouse model of MS via tolerance induction in autoreactive T cells induced by the intravenous infusion
of 500nM carboxylated poly(lactic-co-glycolic acid) (PLG) nanoparticles coupled with or encapsulating myelin
peptides (Ag-PLG). Ag-PLG nanoparticles effectively reduce disease in relapsing-remitting (RR-EAE) and
chronic-progressive (C-EAE) mouse models of experimental autoimmune encephalomyelitis (EAE) by
tolerizing encephalitogenic Th1/17 cells. The Ag-PLG tolerance approach is currently undergoing phase 1
testing in celiac disease patients. Additionally, there are currently no FDA-approved therapies marketed for
promoting remyelination. We have recently found that digoxin, an FDA-approved cardiac glycoside (Na+/K+
ATPase), and miconazole, an FDA-approved anti-fungal agent, promote oligodendrocyte differentiation and
maturation and robustly induce remyelination with negligible side effects in two non-T cell-mediated
demyelination models - cuprizone and DTA-induced mouse demyelinating models. As both autoimmunity and
neurodegeneration underlie MS pathogenesis, effective disease modifying therapies need to both regulate the
immune system and promote restoration of neuronal function, including remyelination. Thus, we will test the
hypothesis that remyelination can be more efficiently induced in mice in which underlying autoimmune
responses are specifically regulated. The proposed research will examine the effects of therapy with
digoxin or miconazole to promote endogenous remyelination by stimulating oligodendrocyte progenitor cells
(OPCs) alone or in combination with Ag-PLG tolerance-based immunotherapy in T cell-mediated demyelinating
disease. The drugs will be tested in two autoimmune-mediated mouse EAE models of relapsing-remitting and
chronic-progressive MS providing the ability to test myelin repair promoting strategies in the two major clinical
disease types observed in MS patients. We hypothesize that since both autoimmunity and neurodegeneration
underlie MS pathogenesis, effective disease modifying therapies need to both regulate the immune system
and promote restoration of neuronal function by stimulating myelin repair. These studies will combine the
complimentary expertise of the Miller lab and collaborators (Drs. Popko and Tesar) in tolerance-based
immunotherapy and molecular aspects of myelination, and will hopefully pave the way for future clinical studies
employing this combinatorial therapeutic approach in MS patients.
StatusActive
Effective start/end date2/11/191/31/21

Funding

  • National Institute of Allergy and Infectious Diseases (5R21AI142059-02)

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