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Characterising skin immune cells to inform development of intradermal vaccines and therapeutics

Ivory, Matthew Owen 2016. Characterising skin immune cells to inform development of intradermal vaccines and therapeutics. PhD Thesis, Cardiff University.
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Abstract

Epidermal Langerhans cells (LCs) and multiple subsets of dermal dendritic cells (dDCs) make skin a valuable route for vaccination, offering the potential for antigen-sparing immunisation. The interconnected immunological functions of dDC subsets and LCs are not fully understood however. This Thesis therefore aimed to explore the interactions of skin immune cells with viral pathogens and vaccines to inform the development of future therapeutics and intradermal vaccines. LCs and dDCs were isolated from ex vivo human skin tissue using a walkout protocol which allowed the enrichment of the migratory cells from the tissue. LCs and dDCs were infected with a lentiviral vector encoding GFP, allowing study of post-entry HIV viral restriction. The study uncovered the existence of a SAMHD-1-independent antiviral factor unique to LCs. LCs and dDCs from ex vivo skin were used to examine the cross-presentation of an inactivated influenza virus-derived matrix peptide to CD8+ T-cells. Two CD11c+ subsets of dDCs were found to potently cross present the antigen. Delivery of VLPs, which lack genetic material, markedly reduced cross-presentation, suggesting that viral genetic material is vital for dDCs to activate cross-presentation pathways. Future work is required to determine if this is true of other influenza peptides or pathogens. Vaccine delivery studies performed using murine and human models found that dDCs were responsible for the greatest uptake of ovalbumin peptide antigen and LCs did not migrate out of the epidermis in the first 4 hours after inactivated influenza virus vaccine delivery respectively. Collectively, this work highlighted the importance of dDCs in antigen uptake and cross-presentation to prime cytotoxic T-cell responses. Innovative delivery methods such as microneedles offer a means of accessing the dermal compartment in a pain-free manner, though further work is required to determine the optimal combination of vaccine formulation and delivery method to harness the immunostimulatory abilities of dDCs.

Item Type: Thesis (PhD)
Date Type: Publication
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: vaccine, Langerhans, dendritic, microneedles, intradermal, therapeutics
Date of First Compliant Deposit: 19 December 2016
Last Modified: 05 Jun 2017 05:48
URI: http://orca-mwe.cf.ac.uk/id/eprint/96969

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