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Title: Advanced adjuvants for antibody production
Author: Rooney, Matthew C. O.
ISNI:       0000 0004 8509 931X
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2020
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Vaccination has significantly reduced the rates of mortality and morbidity however the adjuvants used in modern vaccines preferentially prime the immune response towards specific outcomes that may be disadvantageous. The adjuvant efficiency of the well-established cationic liposomal formulation dimethyldioctadecylammonium-salt (DDA) and trehalose-D-(+)-dibehenate (TDB) with and without encapsulated N-acetyl cysteine (NAC) is explored. The antioxidant NAC reduces disulphide bonds and is a precursor of glutathione. This can be used to influence the immune response by countering reactive oxygen species (ROS) that are key for both innate and adaptive immune responses. Dendritic cells (DCs) are specialised antigen-presenting cells (APCs) and are one of the first involved in humoral immunity. Herein, a representative mouse bone marrow derived DC model for testing the effects of ROS modulators and antigens with DDA:TDB or DDA:TDB-NAC was examined. DDA:TDB-NAC with the test antigen ovalbumin was less toxic and increased cellular pH and activation markers compared to the DDA:TDB formulation. No difference in titre of IgG antibodies to OVA was observed between the two formulations in vivo. NADPH oxidase 2 (NOX2) generates ROS in phagosomes alkalinizing the lumen and altering the activity of proteolytic processing enzymes cathepsins. This changes the degree of antigen processing and potentially immune response. In this study NOX2 deficient DCs did not mature as effectively, possibly due to reduced uptake and changes in pH. DDA:TDB adjuvant formulations were examined using di-sulphide crosslinked collagen II as an antigen to improve a rheumatoid arthritis model. They were more effective than Freund’s regarding cytokine release and IgG1 production however arthritic severity scoring was decreased. Due to its nature the production of antibodies against lipoarabinomannan from tuberculosis is challenging. The possibility of DDA:TDB-Lipoarabinomannan nanoparticles were evaluated and successful binding of LAM to the surface of DDA:TDB was demonstrated along with preferential uptake by DCs.
Supervisor: Griffiths, Helen Sponsor: BBSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral