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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 1 / prevention & control*
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Female
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Glutamate Decarboxylase / administration & dosage
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Glutamate Decarboxylase / genetics
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Glutamate Decarboxylase / therapeutic use
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / therapeutic use
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Injections, Intramuscular
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism
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Interleukin-10 / administration & dosage
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Interleukin-10 / genetics
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Interleukin-10 / therapeutic use
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Interleukin-4 / administration & dosage
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Interleukin-4 / therapeutic use
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Islets of Langerhans / immunology*
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Islets of Langerhans / pathology*
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Islets of Langerhans Transplantation / immunology*
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Islets of Langerhans Transplantation / methods*
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Islets of Langerhans Transplantation / pathology
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Isoenzymes / administration & dosage
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Isoenzymes / genetics
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Isoenzymes / therapeutic use
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Mice
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Mice, Inbred NOD
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Plasmids / administration & dosage
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Plasmids / immunology*
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Plasmids / therapeutic use
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Transplantation, Isogeneic
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Up-Regulation / genetics
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Up-Regulation / immunology
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Vaccines, DNA / administration & dosage
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Vaccines, DNA / immunology*
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Vaccines, DNA / therapeutic use
Substances
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Immunoglobulin Fc Fragments
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Isoenzymes
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Vaccines, DNA
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Interleukin-10
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Interleukin-4
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Interferon-gamma
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Glutamate Decarboxylase
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glutamate decarboxylase 2