title: Microneedle delivery of autoantigen for immunotherapy in type 1 diabetes.
abstract: Antigen specific immunotherapy mediated via the sustained generation of regulatory T cells arguably represents the ideal therapeutic approach to preventing beta cell destruction in type 1 diabetes. However, there is a need to enhance the efficacy of this approach to achieve disease modification in man. Previous studies suggest that prolonged expression of self-antigen in skin in a non-inflammatory context is beneficial for tolerance induction. We therefore sought to develop a dry-coated microneedle (MN) delivery system and combine it with topical steroid to minimise local inflammation and promote prolonged antigen presentation in the skin. Here we show that a combination of surface-modified MNs coated with appropriate solvent systems can deliver therapeutically relevant quantities of peptide to mouse and human skin even with hydrophobic peptides. Compared to conventional "wet" intradermal (ID) administration, "dry" peptide delivered via MNs was retained for longer in the skin and whilst topical hydration of the skin with vehicle or steroid accelerated loss of ID-delivered peptide from the skin, MN delivery of peptide was unaffected. Furthermore, MN delivery resulted in enhanced presentation of antigen to T cells in skin draining lymph nodes (LNs) both 3 and 10days after administration. Repeated administration of islet antigen peptide via MN was effective at reducing antigen-specific T cell proliferation in the pancreatic LN, although topical steroid therapy did not enhance this. Taken together, these data show auto-antigenic peptide delivery into skin using coated MNs results in prolonged retention and enhanced antigen presentation compared to conventional ID delivery and this approach may have potential in individuals identified as being at a high risk of developing type 1 diabetes and other autoimmune diseases.
authors.affiliation: Diabetes Research Group, Institute for Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK; School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK. Electronic address: birchalljc@cf.ac.uk.
authors.forename: James C
authors.initials: JC
authors.lastname: Birchall
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Sion A
authors.initials: SA
authors.lastname: Coulman
authors.affiliation: Diabetes Research Group, Institute for Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Danijela
authors.initials: D
authors.lastname: Tatovic
authors.affiliation: Diabetes Research Group, Institute for Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Diabetes Research Group, Institute for Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: Diabetes Research Group, Institute for Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.affiliation: Diabetes Research Group, Institute for Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Hanna
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D017951:Antigen Presentation / Q000187:drug effects; D001324:Autoantigens / Q000008:administration & dosage* / Q000627:therapeutic use; D001623:Betamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D053379:Chromogranin A / Q000008:administration & dosage* / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008822:Mice, Transgenic; D008845:Microinjections; D008875:Middle Aged; D009339:Needles; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use; D012867:Skin / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D001324:Autoantigens; D053379:Chromogranin A; D010446:Peptide Fragments; C000604951:WE14 protein, mouse; D001623:Betamethasone
keywords: Antigen presentation; Diabetes; Immunotherapy; Microneedle; Skin; Tolerance