title: Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice.
abstract: A deficit in IL-4 production has been previously reported in both diabetic human patients and non-obese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-week old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/IL-4) into 12-week old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford, CA 94305-5166, USA.
authors.forename: Rémi J
authors.initials: RJ
authors.lastname: Creusot
authors.forename: Shahriar S
authors.initials: SS
authors.lastname: Yaghoubi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kodama
authors.forename: Demi N
authors.initials: DN
authors.lastname: Dang
authors.forename: Vu H
authors.initials: VH
authors.lastname: Dang
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006649:Histocompatibility Antigens / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000276:immunology; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
chemical_list: D001786:Blood Glucose; D006649:Histocompatibility Antigens; D015847:Interleukin-4; D012313:RNA