title: A combination dual-sized microparticle system modulates dendritic cells and prevents type 1 diabetes in prediabetic NOD mice.
abstract: We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-β1 or GM-CSF. The combination of Vit D3/TGF-β1 MPs confers an immature and LPS activation-resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-β1 and GM-CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial-based, MP vaccine system to successfully prevent autoimmune diabetes.
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Jamal S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Dolgova
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Chang Qing
authors.initials: CQ
authors.lastname: Xia
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clare-Salzler
authors.affiliation: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA. Electronic address: bgk@ufl.edu.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Keselowsky
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004337:Drug Carriers; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology; D007328:Insulin / Q000494:pharmacology; D019344:Lactic Acid; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010316:Particle Size; D010446:Peptide Fragments / Q000494:pharmacology; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014612:Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D004337:Drug Carriers; D007328:Insulin; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D053773:Transforming Growth Factor beta1; D014612:Vaccines; C097877:insulin B (9-23); D002762:Cholecalciferol; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Dendritic cells; Diabetes; Microparticle; NOD; Prevention; Tolerance
references.citation: J Clin Invest. 1992 Sep;90(3):741-8
references.pmid: 1522229
references.citation: Trends Mol Med. 2009 Feb;15(2):41-9
references.pmid: 19162548
references.citation: J Cell Mol Med. 2014 Oct;18(10):2082-91
references.pmid: 25215657
references.citation: Adv Drug Deliv Rev. 2005 Jan 10;57(3):391-410
references.pmid: 15560948
references.citation: J Autoimmun. 2010 Jun;34(4):408-15
references.pmid: 19931408
references.citation: Cytotherapy. 2010 Oct;12(6):721-34
references.pmid: 20429791
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11270-5
references.pmid: 22745170
references.citation: Adv Drug Deliv Rev. 1998 Jul 6;32(3):225-246
references.pmid: 10837646
references.citation: Hum Vaccin. 2011 Jan 1;7(1):37-44
references.pmid: 21157186
references.citation: Nat Rev Immunol. 2007 Oct;7(10):790-802
references.pmid: 17853902
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2821-6
references.pmid: 17307871
references.citation: Nutr Res Rev. 2007 Jun;20(1):106-18
references.pmid: 19079863
references.citation: Immunol Lett. 2004 Jan 30;91(1):63-9
references.pmid: 14757371
references.citation: Clin Immunol. 2009 May;131(2):260-70
references.pmid: 19171501
references.citation: Semin Immunol. 2006 Apr;18(2):93-102
references.pmid: 16469503
references.citation: Curr Opin Organ Transplant. 2008 Aug;13(4):350-7
references.pmid: 18685329
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788-92
references.pmid: 2886992
references.citation: Immunity. 2011 May 27;34(5):637-50
references.pmid: 21616434
references.citation: Diabetologia. 1980 Sep;19(3):216-21
references.pmid: 6997124
references.citation: Immunol Rev. 2003 Dec;196:109-24
references.pmid: 14617201
references.citation: Diabetes. 1995 Oct;44(10):1176-9
references.pmid: 7556954
references.citation: Blood. 2005 Nov 15;106(10):3490-7
references.pmid: 16030186
references.citation: Diabetes. 2008 Jun;57(6):1544-55
references.pmid: 18316361
references.citation: J Clin Invest. 2001 May;107(10):1275-84
references.pmid: 11375417
references.citation: Nat Mater. 2009 Feb;8(2):151-8
references.pmid: 19136947
references.citation: Methods Mol Biol. 2011;677:303-38
references.pmid: 20941619
references.citation: J Exp Med. 2009 Mar 16;206(3):549-59
references.pmid: 19237601
references.citation: Eur Cytokine Netw. 2002 Jan-Mar;13(1):29-37
references.pmid: 11956018
references.citation: Biomaterials. 2012 Oct;33(29):7221-32
references.pmid: 22796161
references.citation: Diabetes. 2005 Feb;54(2):434-42
references.pmid: 15677501
references.citation: Clin Exp Immunol. 1983 Sep;53(3):605-13
references.pmid: 6352097
references.citation: J Clin Invest. 1997 Sep 15;100(6):1344-8
references.pmid: 9294099
references.citation: Autoimmun Rev. 2006 Jul;5(6):419-23
references.pmid: 16890897
references.citation: Endocrinol Metab Clin North Am. 1999 Dec;28(4):841-64, x
references.pmid: 10609123
references.citation: Diabetes. 2005 May;54(5):1407-14
references.pmid: 15855327
references.citation: J Immunol. 2000 Mar 1;164(5):2405-11
references.pmid: 10679076
references.citation: Microbes Infect. 2005 Jun;7(7-8):1033-9
references.pmid: 15919222
references.citation: J Immunol. 2001 Mar 1;166(5):3499-505
references.pmid: 11207309
references.citation: Diabetes Care. 2011 Sep;34(9):2026-32
references.pmid: 21680720
references.citation: Annu Rev Immunol. 2000;18:767-811
references.pmid: 10837075
references.citation: Transplantation. 2012 Mar 27;93(6):580-8
references.pmid: 22270834
references.citation: J Mater Chem B Mater Biol Med. 2014 May 7;2(17):2562-2574
references.pmid: 24778809
references.citation: Immunity. 2010 Apr 23;32(4):437-45
references.pmid: 20412754
references.citation: Semin Immunol. 2008 Apr;20(2):86-100
references.pmid: 18162407
references.citation: Nat Immunol. 2001 Aug;2(8):675-80
references.pmid: 11477402
references.citation: J Exp Med. 2005 Nov 21;202(10):1387-97
references.pmid: 16301745
references.citation: Pediatr Clin North Am. 2005 Dec;52(6):1553-78
references.pmid: 16301083
references.citation: Curr Opin Immunol. 2007 Feb;19(1):55-62
references.pmid: 17137775
references.citation: Expert Rev Vaccines. 2011 Dec;10(12):1731-42
references.pmid: 22085176
references.citation: Annu Rev Immunol. 2005;23:447-85
references.pmid: 15771578