title: Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model.
abstract: Peptide immunotherapy (PIT) is a targeted therapeutic approach, involving administration of disease-associated peptides, with the aim of restoring antigen-specific immunological tolerance without generalized immunosuppression. In type 1 diabetes, proinsulin is a primary antigen targeted by the autoimmune response, and is therefore a strong candidate for exploitation via PIT in this setting. To elucidate the optimal conditions for proinsulin-based PIT and explore mechanisms of action, we developed a preclinical model of proinsulin autoimmunity in a humanized HLA-DRB1*0401 transgenic HLA-DR4 Tg mouse. Once proinsulin-specific tolerance is broken, HLA-DR4 Tg mice develop autoinflammatory responses, including proinsulin-specific T cell proliferation, interferon (IFN)-γ and autoantibody production. These are preventable and quenchable by pre- and post-induction treatment, respectively, using intradermal proinsulin-PIT injections. Intradermal proinsulin-PIT enhances proliferation of regulatory [forkhead box protein 3 (FoxP3(+))CD25(high) ] CD4 T cells, including those capable of proinsulin-specific regulation, suggesting this as its main mode of action. In contrast, peptide delivered intradermally on the surface of vitamin D3-modulated (tolerogenic) dendritic cells, controls autoimmunity in association with proinsulin-specific IL-10 production, but no change in regulatory CD4 T cells. These studies define a humanized, translational model for in vivo optimization of PIT to control autoimmunity in type 1 diabetes and indicate that dominant mechanisms of action differ according to mode of peptide delivery.
authors.affiliation: Department of Immunobiology, Faculty of Life Science and Medicine, King's College London, UK.
authors.forename: V B
authors.initials: VB
authors.lastname: Gibson
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Nikolic
authors.affiliation: Department of Immunobiology, Faculty of Life Science and Medicine, King's College London, UK.
authors.forename: V Q
authors.initials: VQ
authors.lastname: Pearce
authors.affiliation: Instituto Gulbenkian De Ciencia, Oeiras, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Demengeot
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
authors.affiliation: Department of Immunobiology, Faculty of Life Science and Medicine, King's College London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Peakman
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology*; D011384:Proinsulin / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C556062:IL10 protein, mouse; D010455:Peptides; D016753:Interleukin-10; D007371:Interferon-gamma; D011384:Proinsulin
keywords: T cells; antigens/peptides/epitopes; autoimmunity; diabetes; regulatory T cells