Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells.
Phenotypically "immature" dendritic cells (DCs), defined by low cell surface CD40, CD80, and CD86 can elicit host immune suppression in allotransplantation and autoimmunity. Herein, we report the most direct means of achieving phenotypic immaturity in NOD bone marrow-derived DCs aiming at preventing diabetes in syngeneic recipients. CD40, CD80, and CD86 cell surface molecules were specifically down-regulated by treating NOD DCs ex vivo with a mixture of antisense oligonucleotides targeting the CD40, CD80, and CD86 primary transcripts. The incidence of diabetes was significantly delayed by a single injection of the engineered NOD DCs into syngeneic recipients. Insulitis was absent in diabetes-free recipients and their splenic T cells proliferated in response to alloantigen. Engineered DC promoted an increased prevalence of CD4(+)CD25(+) T cells in NOD recipients at all ages examined and diabetes-free recipients exhibited significantly greater numbers of CD4(+)CD25(+) T cells compared with untreated NOD mice. In NOD-scid recipients, antisense-treated NOD DC promoted an increased prevalence of these putative regulatory T cells. Collectively, these data demonstrate that direct interference of cell surface expression of the major costimulatory molecules at the transcriptional level confers diabetes protection by promoting, in part, the proliferation and/or survival of regulatory T cells. This approach is a useful tool by which DC-mediated activation of regulatory T cells can be studied as well as a potential therapeutic option for type 1 diabetes.
Machen
Jennifer
J
Diabetes Institute, Department of Pediatrics, University of Pittsburgh School of Medicine, PA 15213, USA.
Harnaha
Jo
J
Lakomy
Robert
R
Styche
Alexis
A
Trucco
Massimo
M
Giannoukakis
Nick
N
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007108:Immune Tolerance; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis; D008218:Lymphocytosis / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D011236:Prediabetic State / Q000276:immunology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D021122:Protein Subunits; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D018664:Interleukin-12; D009569:Nitric Oxide