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Microneedle delivery of antigen-specific immunotherapy for Type 1 diabetes

Arikat, Farah 2019. Microneedle delivery of antigen-specific immunotherapy for Type 1 diabetes. PhD Thesis, Cardiff University.
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Abstract

Antigen-specific immunotherapy (ASI) involves induction of tolerance to autoantigens. An important protein in the development of type 1 diabetes (T1D) is the autoantigen, proinsulin (PI), the precursor of insulin. Microneedles (MNs) are micron-sized needles that penetrate into the upper skin layers. MNs provide advantages for autoantigen delivery including targeted delivery to the skin’s dendritic cells (DCs), with minimal inflammation. The aim of this Thesis was to develop a PI-coated solid MN system and investigate the potential of this system to induce peripheral tolerance in the non-obese diabetic (NOD) mouse model of T1D. A highly concentrated PI MN coating formulation was developed containing the PI, diluent and a surfactant. The formulation enabled uniform and reproducible coating of the PI on to MNs. Delivery of PI from the MN system was investigated in mouse skin. MN application method and duration were optimised and resulted in skin puncture and reproducible delivery of PI to the skin. In vitro studies identified the insulin-reactive G9 CD8+ T cell as an appropriate biological readout for PI delivery. In vivo delivery studies indicated that MNdelivered PI was delivered to the skin and subsequently processed by DCs into PI peptides, which were cross-presented in the skin draining lymph nodes to adoptively transferred G9 CD8+ T cells. This demonstrated that the PI-coated MN system has potential for inducing peripheral tolerance in the NOD mouse. T1D development was significantly delayed in NOD SCID mice that received cells from PI-treated NOD mice and cells from diabetic NOD mice (experimental group). However, no statistically significant difference in time to T1D development was observed between the experimental group and the control NOD SCID mice that received cells from untreated NOD mice and diabetic NOD mice. Further investigation of the dosage and dosing frequency of PI using the coated MN system is, therefore, warranted.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: Microneedle; Immunotherapy; Proinsulin; Diabetes; Skin; Tolerance
Funders: Engineering and Physical Sciences Research Council
Date of First Compliant Deposit: 25 January 2019
Last Modified: 25 Jan 2019 11:20
URI: http://orca-mwe.cf.ac.uk/id/eprint/118826

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