Co-Delivery of Immunomodulators and Autoantigen as Antigen-Specific Immunotherapy for the Treatment of a Murine Model of Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is an autoimmune disease characterized by the breakdown of immune tolerance towards autoantigen in the myelin sheath surrounding the neurons. Current therapies for MS and other autoimmune diseases focus on treating the symptoms and not the cause of the disease. A major setback in improving current therapeutics for autoimmunity is the lack of antigen specificity. Successful antigen-specific immunotherapy (ASIT) would allow for improved treatment of autoimmune diseases. This thesis investigates the creation of ASIT for autoimmunity through the co-delivery of an immunomodulator and autoantigen. First, immunomodulatory peptides targeting the B7 costimulatory pathway and cell adhesion were tested for their ability to suppress a murine model of MS, experimental autoimmune encephalomyelitis (EAE), utilizing a co-delivery vehicle developed in our lab, soluble antigen arrays. Peptides targeting different surface markers were all found to suppress EAE when co-delivered with autoantigen, demonstrating the ability of different immunomodulators to create effective ASIT. Expanding upon the idea of combinational ASIT, eleven different small molecules immunomodulators were screened for properties indicative of autoimmune suppression in an antigen-specific splenocyte system. This screen revealed that several compounds, most notably dexamethasone, had the ability to skew the antigen-specific immune response towards autoimmune suppression. The ability of dexamethasone to act as an effective immunomodulator in ASIT for autoimmunity was confirmed in vivo in the treatment of EAE. Co-delivery of dexamethasone and autoantigen in an oil-in-water emulsion, incomplete Freund’s adjuvant, was found to suppress EAE and shift the immune response. Overall, the results presented dissertation provide evidence for the successful creation of ASIT for autoimmunity by combining immunomodulator and autoantigen.