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Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
Published on: May 6, 2013
Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
Wenxian Fu1, Julia Farache1, Susan M Clardy2
1Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
Abstract:
Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a 'combination therapy' currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration.
Insights
A novel drug, I-BET151, stops type-1 diabetes development in mice by reducing islet inflammation and promoting beta-cell regeneration. This epigenetic modifier offers a potential new therapeutic strategy for autoimmune diabetes.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Epigenetic modifiers are promising anti-tumor agents.
- Their impact on autoimmune diseases, like type-1 diabetes, is largely unexplored.
Purpose of the Study:
- To investigate the effects of I-BET151, a bromodomain inhibitor, on type-1 diabetes development.
- To elucidate the mechanisms underlying I-BET151's therapeutic potential in autoimmune diabetes.
Main Methods:
- Treatment of non-obese diabetic (NOD) mice with I-BET151.
- Analysis of insulitis, T cell transcriptomes, macrophage phenotype, and pancreatic islet cell regeneration.
- Assessment of NF-κB pathway activity.
Main Results:
- I-BET151 irreversibly suppressed type-1 diabetes development and cleared insulitis in NOD mice.
- The drug induced an anti-inflammatory phenotype in pancreatic macrophages, affecting the NF-κB pathway.
- I-BET151 promoted islet beta-cell regeneration and expression of key differentiation/function genes, independent of T cell infiltration.
Conclusions:
- I-BET151 demonstrates a novel dual mechanism for treating type-1 diabetes: reducing inflammation and enhancing beta-cell regeneration.
- This epigenetic approach offers a potential 'combination therapy' strategy for autoimmune diabetes.
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