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Al-Zahri, Reem (2018) Immune modulatory properties of nanoparticles on human dendritic cells. PhD thesis, University of Nottingham.

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Abstract

Dendritic cells (DCs) are professional antigen presenting cells that play a potent role as a key link between innate and adaptive immunity. Given the quintessential role of DCs in orchestrating immune responses, better understanding of conditions that control DC function could provide opportunities for developing new treatment strategies for infectious and autoimmune diseases. Recently, there is a growing interest to utilize nanoparticles (NPs) with diverse chemistry, size and other physicochemical attributes in vaccination, drug delivery systems, and diagnostics. There is emerging evidence for the effect of NPs size, shape, and other physiochemical properties on cellular responses; however, the impact of NPs on the immune system, and particularly the function and phenotype of DCs, is yet to be fully understood. The overall aim of this study was investigating the influence of different properties of NPs on DC phenotype, cytokine profile, function (e.g. endocytic ability) and metabolic profile. This was done by exposing DCs to a defined concentration of NPs, particularly, PLGA NPs, Silica (SNPs) and polystyrene (PS NPs), which were successfully fabricated or commercially sourced, respectively. The findings clearly demonstrated that particle size and the choice of material can affect different aspects of DC phenotype. While spherical Silica and PLGA NPs of 100 nm and 160 nm size range respectively do not change DC phenotype and function (endocytic ability), PS NPs of similar size and PLGA NPs of 500 nm size induce significant changes in DC phenotype and function. PS NPs of 150 nm and 200 nm size significantly suppress the expression of mannose receptor (MR or CD206) on DCs by around 90%-80% without affecting their viability, maturation status or cytokine profile. In addition, PLGA NPs of 500 nm size induced DC maturation as evidenced by high levels of CD83 expression.

Accordingly, the impact of NP properties on one DC key function, namely endocytic ability, was investigated. Interestingly, the data showed that PS NPs (150 nm/200 nm) and PLGA NPs (500 nm) significantly influenced this function. While PLGA NPs (160 nm) and SNPs (100 nm/500 nm) did not induce changes in DC endocytic ability. Furthermore, with regard to NP cellular uptake by antigen presenting cells, our data demonstrated that specific NP size and material (PLGA NPs 120 nm) reflect a preferential uptake by DCs compared to 500 nm PLGA NPs. By contrast, macrophages (Mϕs) showed similar trend of uptake for both PLGA NP sizes. Our data also showed the role of NP surface modification on cellular uptake. Modified SNPs to positive charge showed high percentage of uptake by DCs.

Examining the impact of NP material type (PLGA NPs and PS NPs) on DC metabolic profile could provide valuable information about the impact of NPs on overall DC function in an unbiased manner. The metabolomics profile data showed a significant increase in glycolysis pathway upon stimulation by PLGA NPs and PS NPs, as indicated by lactate production. Also, significant changes were observed in DC purine and amino acid metabolism upon PLGA NPs and PS NPs treatment, respectively.

In conclusion, this study gives new insights into understanding how DCs react to different properties of NPs, which can pave the way for the rational design of NPs with tuneable immune-modulatory properties for immunotherapy applications.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Ghaemmaghami, Amir Aylott, Jonathan
Keywords:	Dendritic cells; Nanoparticles; Dendritic cell phenotype; Cytokine profile; Metabolic profile
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	55418
Depositing User:	Alzahri, Reem
Date Deposited:	12 Apr 2019 12:12
Last Modified:	13 Dec 2020 04:30
URI:	https://eprints.nottingham.ac.uk/id/eprint/55418

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