Fc Coated Micro/nanoparticles for Humoral Immune System Modulation

Advisor:

Todd Sulchek, Ph.D., Mechanical Engineering, Georgia Institute of Technology

Committee:

Julia Babensee, Ph.D., Biomedical Engineering, Georgia Institute of Technology

Julie Champion, Ph.D., Chemical and Biomolecular Engineering, Georgia Institute of Technology

 Andrés García, Ph.D., Mechanical Engineering, Georgia Institute of Technology

David M. White, D.V.M., Ph.D., DACVM, United States Department of Agriculture 

The body’s humoral immune response plays a larger role beyond screening for invading pathogens as it is also vital for tissue regeneration, drug delivery, and vaccine processing. The immune system operates within a sophisticated feedback loops, and as such, reagents which may alter it in a tunable manner offer promise to study the immune system as well as engineer specific responses for therapeutic effect. While a strong initial input can sway the response to one of two extremes (pro- or anti-inflammatory), an extreme response is not always required or desired in the case of immunocompromised patients. Therefore, we set out to derive a novel biomaterials platform to alter the immune response in a tunable manner. Antibodies are not only the workhorses of the adaptive immune response but are also powerful immunomodulators through their Fc (constant fragment) regions. By coating microparticles with Fc ligands in variable surface densities, we were able to utilize the sensitivity of multivalent signaling to tune the response of the immune response. Microparticle size was also varied to decouple the effects of physical versus biochemical signaling.

 The goal of this thesis was to analyze the effects of Fc coated particles on two major components of the humoral immune responses: macrophages and the complement system. We first looked at the mechanical response of macrophages through phagocytosis and found that both Fc density and microparticle size had significant impacts on macrophage phagocytosis. These results also provide a particle delivery “toolbox” for future applications. We then analyzed the downstream effects of Fc particles on macrophage phenotype and on phenotype plasticity. This showed that the addition of Fc particles lead to increased production of TNFα and IL-12 and inverted the response of LPS treated macrophages. Finally, we applied our particles to activate the complement system, an often overlooked cascade of serum protein activation that results in bacterial cell lysis. Cleaved components of the complement system are also powerful chemokines and can act as a vaccine adjuvant. Fc density on particles played a large role in complement system activation, both through the classical and alternative pathway, as it lead to a binary response for smaller particles and a tunable response for larger particles. We then applied these results to create a novel form of antibiotic by using Fc particles to direct complement-mediated bacterial cytotoxicity. The use of immune activation by Fc particles was also applied to better understand and improve the tuberculosis vaccine. Our findings are significant to the biomaterials and immunology fields as we showed that Fc microparticles can generally be used to alter the immune response in a tunable manner for a broad range of applications, as well answering fundamental immunology questions.