title: More stringent conditions of plasmid DNA vaccination are required to protect grafted versus endogenous islets in nonobese diabetic mice.
abstract: Recurrent autoimmune destruction of the insulin-producing beta cells is a key factor limiting successful islet graft transplantation in type I diabetic patients. In this study, we investigated the feasibility of using an Ag-specific plasmid DNA (pDNA)-based strategy to protect pro-islets that had developed from a neonatal pancreas implanted under the kidney capsule of nonobese diabetic (NOD) mice. NOD recipient mice immunized with pDNA encoding a glutamic acid decarboxylase 65 (GAD65)-IgFc fusion protein (JwGAD65), IL-4 (JwIL4), and IL-10 (pIL10) exhibited an increased number of intact pro-islets expressing high levels of insulin 15 wk posttransplant, relative to NOD recipient mice immunized with pDNA encoding a hen egg lysozyme (HEL)-IgFc fusion protein (JwHEL)+JwIL4 and pIL10 or left untreated. Notably, the majority of grafted pro-islets detected in JwGAD65+JwIL4- plus pIL10-treated recipients was free of insulitis. In addition, administration of JwGAD65+JwIL4+pIL10 provided optimal protection for engrafted islets compared with recipient NOD mice treated with JwGAD65+JwIL4 or JwGAD65+pIL10, despite effective protection of endogenous islets mediated by the respective pDNA treatments. Efficient protection of pro-islet grafts correlated with a marked reduction in GAD65-specific IFN-gamma reactivity and an increase in IL-10-secreting T cells. These results demonstrate that pDNA vaccination can be an effective strategy to mediate long-term protection of pro-islet grafts in an Ag-specific manner and that conditions are more stringent to suppress autoimmune destruction of grafted vs endogenous islets.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Curriculum in Oral Biology, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Seifarth
authors.forename: Shannon
authors.initials: S
authors.lastname: Pop
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Wong
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D016753:Interleukin-10 / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D015847:Interleukin-4 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods* / Q000473:pathology; D007527:Isoenzymes / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D014185:Transplantation, Isogeneic; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D007141:Immunoglobulin Fc Fragments; D007527:Isoenzymes; D019444:Vaccines, DNA; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2