Abstract
BackgroundWe and others have previously demonstrated that treatment with bone marrow derived DC genetically modified to express IL-4 reduce disease pathology in mouse models of collagen-induced arthritis and delayed-type hypersensitivity. Moreover, treatment of normoglycemic NOD mice with bone marrow derived DC, genetically modified to express interleukin 4 (IL-4), reduces the onset of hyperglycemia in a significant number of animals. However, the mechanism(s) through which DC expressing IL-4 function to prevent autoimmune diabetes and whether this treatment can reverse disease in pre-diabetic NOD mice are unknown.Methodology/Principal FindingsDC were generated from the bone marrow of NOD mice and transduced with adenoviral vectors encoding soluble murine IL-4 (DC/sIL-4), a membrane-bound IL-4 construct, or empty vector control. Female NOD mice were segregated into normoglycemic (<150mg/dL) and prediabetic groups (between 150 and 250 mg/dL) on the basis of blood glucose measurements, and randomized for adoptive transfer of 106 DC via a single i.v. injection. A single injection of DC/sIL-4, when administered to normoglycemic 12-week old NOD mice, significantly reduced the number of mice that developed diabetes. Furthermore, DC/sIL-4, but not control DC, decreased the number of mice progressing to diabetes when given to prediabetic NOD mice 12–16 weeks of age. DC/sIL-4 treatment also significantly reduced islet mononuclear infiltration and increased the expression of FoxP3 in the pancreatic lymph nodes of a subset of treated animals. Furthermore, DC/sIL-4 treatment altered the antigen-specific Th2:Th1 cytokine profiles as determined by ELISPOT of splenocytes in treated animals.ConclusionsAdoptive transfer of DC transduced to express IL-4 into both normoglycemic and prediabetic NOD mice is an effective treatment for T1D.
Highlights
Type I diabetes (T1D) is a polygenic autoimmune disease characterized by destruction of insulin-secreting b-cells in the islets of Langerhans by a chronic inflammatory infiltrate
We further demonstrate that dendritic cell (DC)/sIL-4 reduce the progression to overt hyperglycemia when administered to 12–16 week-old prediabetic nonobese diabetic (NOD) mice that already have impaired responses to glucose challenge
We and others have demonstrated previously that bone marrow derived DC genetically modified to express interleukin 4 (IL-4) reduce disease pathology in mouse models of collagen-induced arthritis and delayed-type hypersensitivity [19,20]
Summary
Type I diabetes (T1D) is a polygenic autoimmune disease characterized by destruction of insulin-secreting b-cells in the islets of Langerhans by a chronic inflammatory infiltrate. In both humans and the nonobese diabetic (NOD) mouse, destructive insulitis is predominantly a T-cell mediated phenomenon, but other cells types, such as NKT cells and antigen presenting cells (APC), play important roles in modulating disease onset and progression [1,2,3]. We and others have previously demonstrated that treatment with bone marrow derived DC genetically modified to express IL-4 reduce disease pathology in mouse models of collagen-induced arthritis and delayed-type hypersensitivity. The mechanism(s) through which DC expressing IL-4 function to prevent autoimmune diabetes and whether this treatment can reverse disease in pre-diabetic NOD mice are unknown
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