Engineering biomaterials to promote systemic, antigen-specific tolerance
Tostanoski, Lisa Hoban
Jewell, Christopher M
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In autoimmune diseases, such as multiple sclerosis (MS) and type 1 diabetes, the immune system incorrectly identifies and attacks “self” molecules. Existing therapies have provided important benefits, but are limited by off-target effects, reduced efficacy as disease progresses, and lack of cure potential, necessitating frequent, life-long dosing. An exciting strategy being explored is the design of vaccine-like therapies that selectively reprogram immune responses to self-molecules. This approach could, for example, control the attack of myelin – the protective coating around neurons – that occurs during MS, without leaving patients immunocompromised. However, the realization of this idea has proven difficult; once injected, conventional approaches do not provide control over the combinations, concentrations, and kinetics of signals that reach key tissues that orchestrate immune responses, such as lymph nodes (LNs). Biomaterials have emerged as a promising strategy to confront this challenge, offering features including co-delivery of cargos and controlled release kinetics. The research in this dissertation harnesses biomaterials to develop novel strategies to promote effective, yet selective control of autoimmunity, termed antigen-specific tolerance. In the first aim, direct injection was used to deposit degradable microparticles in LNs, enabling local controlled release of combinations of myelin peptide and Rapamycin, a drug shown to promote regulatory immune function. This work demonstrates the potency of intra-LN delivery in mouse models of MS, as a single dose of co-loaded microparticles permanently reversed disease-induced paralysis in a myelin-specific manner. The results also support this approach as a platform to study the link between local LN signaling and resultant responses in non-treated tissues and sites of disease during autoimmunity. In the second aim, myelin peptide and GpG, a regulatory ligand of an inflammatory pathway overactive in mouse models and patients with autoimmunity, were self-assembled. This approach generated microcapsules that mimic attractive features of conventional biomaterials, but eliminate synthetic carrier components that can complicate rational design and, due to intrinsic inflammatory properties, might exacerbate autoimmunity. These materials promoted tolerance in mouse cells, mouse models of MS, and samples from human MS patients. Together, these strategies could offer novel, modular approaches to combat autoimmune diseases and inform design criteria for future therapies.