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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.
