Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.

Abstract

SummaryDiabetes in nonobese diabetic (NOD) mice is a T cell-dependent autoimmune disease. The destructive activities of autoreactive T cells have been shown to be tightly regulated by effector molecules. In particular, T helper (Th) 1 cytokines have been linked to diabetes pathogenesis, whereas Th2 cytokines and the cells that release them have been postulated to be protective from disease. To test this hypothesis, we generated transgenic NOD mice that express interleukin (IL) 4 in their pancreatic [3 cells under the control of the human insulin promoter. We found that transgenic NOD-IL-4 mice, both females and males, were completely protected from insulitis and diabetes. Induction of functional tolerance to islet antigens in these mice was indicated by their inability to reject syngeneic pancreatic islets and the failure of diabetogenic spleen cells to induce diabetes in transgenic NOD-IL-4 recipients. Interestingly, however, islet expression of IL-4 was incapable of preventing islet rejection in overfly diabetic NOD recipient mice. These results demonstrate that the Th2 cytokine IL-4 can prevent the development of autoimmunity and destructive autoreactivity in the NOD mouse. Its ability to regulate the disease process in the periphery also indicates that autoimmune diabetes in NOD mice is not a systemic disease, and it can be modulated from the islet compartment.

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

“…Interestingly, we previously have reported that the expression of GM-CSF in pancreatic gcells does not trigger diabetes in BALB/c mice [41], suggesting that genetic predisposition determines the specific peptide antigens to be presented precipitating clinical diabetes. In addition, preliminary observations showed that in a functionally tolerant model (NOD-IL-4) [42], pancreatic expression of GM-CSF can lead to the appearance of clinical disease in both, females and males, suggesting that affecting antigen presentation can precipitate disease in a non-pathogenic environment. Together, our data are consistent with recent findings showing that DC vaccination consistently triggers clinical autoimmunity in genetically susceptible subjects [22].…”

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

“…Consistent with this view, efficient induction of regulatory Th2 cells in NOD mice has been achieved by systemic treatment with IL-4 or its local expression in pancreatic g -cells in insulin-promoter-IL-4 transgenic mice [14,15]. Based on the Th1/Th2 paradigm, it has been postulated that IL-4 induces a shift in the balance of anti-islet T cells from the pathogenic Th1 toward a less harmful Th2 phenotype.…”

Immortalized Myeloid Suppressor Cells Trigger Apoptosis in Antigen-Activated T Lymphocytes

“…When transgenically expressed in the pancreatic ␤-cells of nonobese diabetic mice or in the CNS of SJL/J mice, IL-4 prevented autoimmune diabetes and experimental allergic encephalomyelitis development, respectively (30,31). APC alternatively activated by IL-4 might thus play a role in controlling the response of T lymphocytes to Ags presented by peripheral tissues.…”