Local administration of biomaterials for inducing antigen-specific immune tolerance

Yuan-Ping (Peter) Li

doi:10.17918/00000388

Current treatment options for autoimmune conditions most commonly employ the use of nonspecific immunosuppressive agents that have significant adverse side effects. Ideally, the goal of autoimmune therapies is to achieve lasting autoantigen-specific tolerance. Nanoparticle (NP)-based therapies have recently shown promise in several animal models, but unfortunately, none have yet been validated in humans, and a deeper understanding of how different nanomaterials affect tolerogenic pathways is still needed. In this thesis, immune system interactions with local subcutaneous administrations of different materials are studied in the context of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, with the ultimate goal of creating and optimizing treatments for autoimmunity. First, a simple subcutaneous injection of a nanoparticle fabricated from PLGA-PEG block copolymer containing only antigen was found to be sufficient to dramatically ameliorate EAE symptoms. The tolerogenic capability of this particle was surprising due to the lack of any tolerogenic drug and because previous studies using PLGA alone did not significantly ameliorate disease. Thus, it was hypothesized that intrinsic properties of PLGA-PEG facilitated tolerogenic responses in ways that other polymers do not. This provided the opportunity to directly compare the effects of PLGA-PEG, PLGA, and partial PLGA/PLGA-PEG nanoparticles on treating EAE and their in vitro and in vivo responses. PLGA-PEG-NPs ameliorated EAE in both an antigen- and material-specific manner. The particles also demonstrated decreased complement activation, increased spleen and lymph node localization, and decreased activation of co-stimulatory molecules in dendritic cells in vivo. Mice successfully treated with the PLGA-PEG-NPs exhibited decreased IL-17 inflammatory cytokine production in response to antigen restimulation ex vivo. In an effort to develop a platform to study local cell recruitment and to further improve tolerogenic responses, a macroporous alginate-based polymeric scaffold system was created. When incorporated with the cytokine GM-CSF, this system demonstrated the ability to recruit significant populations of dendritic cells in vivo, which are the most important cells in immunomodulation. The addition of antigen-loaded PLGA-PEG-NPs allowed the system to also reverse symptoms of EAE after the onset of disease. However, the scaffold system failed to demonstrate an improvement over PLGA-PEG-NPs alone. Overall, these studies will hopefully pave the way for future iterations of scaffold-based autoimmune treatments, a greater understanding of PLGA-based materials for inducing tolerance, and a promising and simple PLGA-PEG nanoparticle for treating autoimmunity.

Local administration of biomaterials for inducing antigen-specific immune tolerance

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Local administration of biomaterials for inducing antigen-specific immune tolerance

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