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Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes.
Citation | “Increased Β-Cell Proliferation Before Immune Cell Invasion Prevents Progression Of Type 1 Diabetes.”. Nature Metabolism, pp. 509-518. . |
Center | Joslin Diabetes Center |
Author | Ercument Dirice, Sevim Kahraman, Dario F De Jesus, Abdelfattah El Ouaamari, Giorgio Basile, Rocky L Baker, Burcu Yigit, Paul D Piehowski, Mi-Jeong Kim, Alexander J Dwyer, Raymond W S Ng, Cornelia Schuster, Heidrun Vethe, Tijana Martinov, Yuki Ishikawa, Adrian Kee Keong Teo, Richard D Smith, Jiang Hu, Kathryn Haskins, Thomas Serwold, Wei-Jun Qian, Brian T Fife, Stephan Kissler, Rohit N Kulkarni |
Abstract |
Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D. Here we report that enhancing β-cell mass early in life, in two models of female NOD mice, results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. The animals displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival in the NOD-LIRKO model. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented development of diabetes in pre-diabetic NOD mice. A significant increase in the splenic CD4CD25FoxP3 regulatory T-cell (Treg) population was observed to underlie the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D. |
Year of Publication |
2019
|
Journal |
Nature metabolism
|
Volume |
1
|
Issue |
5
|
Number of Pages |
509-518
|
Date Published |
05/2019
|
ISSN Number |
2522-5812
|
DOI |
10.1038/s42255-019-0061-8
|
Alternate Journal |
Nat Metab
|
PMID |
31423480
|
PMCID |
PMC6696912
|
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