342641 event 1415294411 1475892609 Patricia M. Pacheco
BioE Ph.D. Dissertation Defense
Date: November 10, 2014
Time: 9:00am
Location: Marcus Nanotechnology Bldg 1117

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

Fc Coated Micro/nanoparticles for Humoral Immune System Modulation

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.

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