PMID- 31119191 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 2373-9878 (Print) IS - 2373-9878 (Electronic) IS - 2373-9878 (Linking) VI - 5 IP - 5 DP - 2019 May 13 TI - Dual-Sized Microparticle System for Generating Suppressive Dendritic Cells Prevents and Reverses Type 1 Diabetes in the Nonobese Diabetic Mouse Model. PG - 2631-2646 LID - 10.1021/acsbiomaterials.9b00332 [doi] AB - Antigen specificity is a primary goal in developing curative therapies for autoimmune disease. Dendritic cells (DCs), as the most effective antigen presenting cells in the body, represent a key target to mediate restoration of antigen-specific immune regulation. Here, we describe an injectable, dual-sized microparticle (MP) approach that employs phagocytosable approximately 1 mum and nonphagocytosable approximately 30 mum MPs to deliver tolerance-promoting factors both intracellularly and extracellularly, as well as the type 1 diabetes autoantigen, insulin, to DCs for reprogramming of immune responses and remediation of autoimmunity. This poly(lactic-co-glycolic acid) (PLGA) MP system prevented diabetes onset in 60% of nonobese diabetic (NOD) mice when administered subcutaneously in 8 week old mice. Prevention of disease was dependent upon antigen inclusion and required encapsulation of factors in MPs. Moreover, administration of this "suppressive-vaccine" boosted pancreatic lymph node and splenic regulatory T cells (Tregs), upregulated PD-1 on CD4(+) and CD8(+) T cells, and reversed hyperglycemia for up to 100 days in recent-onset NOD mice. Our results demonstrate that a MP-based platform can reeducate the immune system in an antigen-specific manner, augment immunomodulation compared to soluble administration of drugs, and provide a promising alternative to systemic immunosuppression for autoimmunity. FAU - Lewis, Jamal S AU - Lewis JS AD - J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, Florida 32611, United States. AD - OneVax, LLC, 12085 Research Drive, Alachua, Florida 32615, United States. AD - Department of Biomedical Engineering, University of California-Davis, One Shields Avenue, Davis, California 95616, United States. FAU - Stewart, Joshua M AU - Stewart JM AD - J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, Florida 32611, United States. FAU - Marshall, Gregory P AU - Marshall GP AD - OneVax, LLC, 12085 Research Drive, Alachua, Florida 32615, United States. FAU - Carstens, Matthew R AU - Carstens MR AD - J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, Florida 32611, United States. FAU - Zhang, Ying AU - Zhang Y AD - J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, Florida 32611, United States. FAU - Dolgova, Natalia V AU - Dolgova NV AD - J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, Florida 32611, United States. FAU - Xia, Changqing AU - Xia C AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. FAU - Brusko, Todd M AU - Brusko TM AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. FAU - Wasserfall, Clive H AU - Wasserfall CH AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. FAU - Clare-Salzler, Michael J AU - Clare-Salzler MJ AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. FAU - Atkinson, Mark A AU - Atkinson MA AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. AD - Department of Pediatrics, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. FAU - Keselowsky, Benjamin G AU - Keselowsky BG AD - J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, Florida 32611, United States. AD - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32611, United States. LA - eng GR - R01 DK098589/DK/NIDDK NIH HHS/United States GR - T32 DK108736/DK/NIDDK NIH HHS/United States GR - R43 DK100132/DK/NIDDK NIH HHS/United States GR - R01 DK091658/DK/NIDDK NIH HHS/United States GR - R01 AI133623/AI/NIAID NIH HHS/United States GR - R56 DK091658/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20190326 PL - United States TA - ACS Biomater Sci Eng JT - ACS biomaterials science & engineering JID - 101654670 PMC - PMC6518351 COIS- The authors declare the following competing financial interest(s): J.S.L. and G.P.M. conducted a portion of the reported experiments while employed by OneVax, LLC. C.H.W., T.M.B., M.A.A., and B.G.K. are cofounders of OneVax, LLC, a preclinical biotechnology company with interest in this technology. The authors declare that no other relevant conflicts of interest exist. EDAT- 2019/05/24 06:00 MHDA- 2019/05/24 06:01 PMCR- 2019/05/15 CRDT- 2019/05/24 06:00 PHST- 2019/03/07 00:00 [received] PHST- 2019/03/26 00:00 [accepted] PHST- 2019/05/24 06:00 [entrez] PHST- 2019/05/24 06:00 [pubmed] PHST- 2019/05/24 06:01 [medline] PHST- 2019/05/15 00:00 [pmc-release] AID - 10.1021/acsbiomaterials.9b00332 [doi] PST - ppublish SO - ACS Biomater Sci Eng. 2019 May 13;5(5):2631-2646. doi: 10.1021/acsbiomaterials.9b00332. Epub 2019 Mar 26.