Fighting Fire with Format: Exploiting Autoantigen Delivery to Combat Autoimmunity

Abstract

There is a dire need for next-generation approaches to treating autoimmune disease that can potently inhibit the autoreactive destruction of host tissue while conserving protective immune functions. Antigen-specific immunotherapies (ASIT) offer such promise by harnessing the same pathogenic epitopes attacked in autoimmunity to selectively suppress the autoreactive cells that cause disease. Formatting autoantigen for ASIT is not trivial, as no clinical immunotherapies of this class are currently approved for treating autoimmune disease despite decades of attempts. This dissertation sought to explore physical and chemical determinants of efficacy in ASITs as a contribution toward fostering a future of precisely tailored autoimmune interventions. In these works, three autoantigen formats are explored: soluble, particulate, and surface delivery – each within the context of murine experimental autoimmune encephalomyelitis (EAE). In chapter 2, the soluble antigen array (SAgA) was adopted as a platform to investigate the role of antigen valency in evoking B cell anergy to promote tolerance among mixed splenocytes. Analysis of SAgAs presenting discrete autoantigen valencies revealed that low-valency (but not monovalent) autoantigen was most capable of inhibiting B cell calcium mobilization, and this inhibition predicted tolerogenic effects in a mixed population of splenocytes. In chapter 3, particulate autoantigen delivery was explored by formulating a “functional” delivery system consisting of an antioxidant vitamin E emulsion. This formulation proved capable to suppress EAE in vivo, but mechanistic analyses suggested a driver of effect that differed from the originally hypothesized antioxidant function. These results motivated the invention of the antigen-specific immune decoys (ASIDs) reported in chapters 4 and 5. ASIDs were comprised of autoantigen restricted onto the surface of microporous collagenous biomaterials. Peptide-epitope decorated constructs prevented EAE in vivo by intercepting and exhausting autoreactive cells. Chapter 5 was an extension of this work, where polyantigenic ASIDs were fabricated to present a comprehensive palette of autoantigens and account for the heterogeneity of authentic disease. Though capable of amplifying discrete antigen-specific cell subsets ex vivo, polyantigenic ASIDs apparently did not induce cellular exhaustion and failed to attenuate EAE as a result. Together, these works emphasize the importance of characteristics such as antigen valency and context. The ongoing exploration of the ASID platform provides a foundation for assessing the utility of engineered local microenvironments in immune-mediated disease.