A combination hydrogel microparticle-based vaccine prevents type 1 diabetes in non-obese diabetic mice.
Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-inducing pathway has proven difficult. To address this hurdle, we developed a vaccine based-approach comprised of two synthetic controlled-release biomaterials, poly(lactide-co-glycolide; PLGA) microparticles (MPs) encapsulating denatured insulin (key self-antigen in type 1 diabetes; T1D), and PuraMatrix(TM) peptide hydrogel containing granulocyte macrophage colony-stimulating factor (GM-CSF) and CpG ODN1826 (CpG), which were included as vaccine adjuvants to recruit and activate immune cells. Although CpG is normally considered pro-inflammatory, it also has anti-inflammatory effects, including enhancing IL-10 production. Three subcutaneous administrations of this hydrogel (GM-CSF/CpG)/insulin-MP vaccine protected 40% of NOD mice from T1D. In contrast, all control mice became diabetic. In vitro studies indicate CpG stimulation increased IL-10 production, as a potential mechanism. Multiple subcutaneous injections of the insulin containing formulation resulted in formation of granulomas, which resolved by 28 weeks. Histological analysis of these granulomas indicated infiltration of a diverse cadre of immune cells, with characteristics reminiscent of a tertiary lymphoid organ, suggesting the creation of a microenvironment to recruit and educate immune cells. These results demonstrate the feasibility of this injectable hydrogel/MP based vaccine system to prevent T1D.
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32611, USA.
Young Mee
YM
Yoon
J. Crayton Pruitt Family Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, FL 32611, USA.
Jamal S
JS
Lewis
J. Crayton Pruitt Family Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, FL 32611, USA.
Matthew R
MR
Carstens
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32611, USA.
Martha
M
Campbell-Thompson
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32611, USA.
Clive H
CH
Wasserfall
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32611, USA.
Mark A
MA
Atkinson
J. Crayton Pruitt Family Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, FL 32611, USA.
Benjamin G
BG
Keselowsky
D000276:Adjuvants, Immunologic; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry; D006099:Granuloma / Q000473:pathology; D020100:Hydrogels / Q000737:chemistry*; D007328:Insulin / Q000737:chemistry / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014612:Vaccines / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001786:Blood Glucose; D020100:Hydrogels; D007328:Insulin; D009838:Oligodeoxyribonucleotides; D014612:Vaccines; D016753:Interleukin-10; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor