Date of Award
12-1-2023
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Biomedical Sciences
Dissertation/Thesis Chair
Nicholas J Mantis
Committee Members
Kathleen A McDonough, Bruce J Herron, William T Lee, Eric J Yager, James R Drake
Keywords
antibody, immunity, mucosal, respiratory, ricin, vaccination
Subject Categories
Immunology of Infectious Disease
Abstract
Ricin toxin (RT) is generated in the seeds of Ricinus communis. The highly potent toxin is comprised of two subunits, RTA and RTB. RT enters cells using RTB before RTA separates itself and inactivates the ribosome, inducing cell stress, inflammation, and eventual death. RT is particularly damaging in the respiratory tract, where intoxication induces an inflammatory cytokine storm.Though there are currently no therapeutics for RT intoxication, our group has generated and characterized a wide variety of monoclonal antibodies (mAbs) against RT. Among the top candidates in our collection are the IgGs PB10 and SylH3. Previous studies have demonstrated their exceptional neutralizing capabilities, and improved efficacy when provided together. One potential prophylactic use of these mAbs is in combination with RT as an immune complex (IC). Studies utilizing mAb ICs to induce adaptive responses have been emerging with compelling results, allowing for “attenuated” antigen administration. Another point of interest in RT therapeutic development has been mucosal vaccines. The majority of pathogens are first encountered at a mucosal tissue, yet the current administration of vaccines is intramuscular. Mucosal vaccination targets mucosal surfaces during immunization to generate local protection, and have been of particular interest in the wake of the COVID-19 pandemic. In this dissertation I sought to evaluate the prophylactic potential of ricin-mAb immune complexes (RICs) for vaccination of the respiratory tract and to uncover the mechanisms underlying this vaccination. Previous work demonstrated that intranasal (i.n.) administration of RICs prevented intoxication, but did not delve further into the fate of RICs or any potential immune response induced. I hypothesized that RICs administration allowed for RT to be processed for antigen presentation, resulting in an adaptive response. In Chapter 3, I show that RICs indeed stimulate a humoral response, with IgG titers detectable as early as 7 days post-immunization and remaining high over several months. I was also able to determine that the more mAbs used, increasing opsonization of RT, the better the adaptive response, and that RICs contribute to more than RT neutralization in this process. Interestingly, RICs do not depend on Fc interactions to mediate immunity. I demonstrate in Chapter 3 that i.n. vaccination with RICs provides superior protection to lethal RT exposure in comparison to i.p. vaccinated animals. In Chapter 4, I further explore the involvement of suspected players in mediating this improved immunity, including helper T (CD4+) cells, finding that CD4+ cells are indeed necessary for RICs vaccination. Finally, I characterize the inflammatory environment stimulated by i.n. delivery of RICs. RICs indeed induced inflammation, albeit to a much lesser degree than RT alone, and this inflammation was primarily contained to the respiratory tract. The results of this dissertation showcase success in my goal of evaluating the prophylactic potential of RICs for mucosal vaccination, and demonstrate their capacity to induce protective vaccination against RT. Collectively, this work serves as a proof-of-concept for the powerful potential of mucosal IC vaccines, as well as a large step forward in the creation of preventive treatments against RT.
Recommended Citation
Tolman, Lindsey Elizabeth, "Induction Of Protective Immunity In The Respiratory Tract With Ricin Toxin Immune Complexes" (2023). Legacy Theses & Dissertations (2009 - 2024). 3255.
https://scholarsarchive.library.albany.edu/legacy-etd/3255
