Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes

Journal Article · Mon May 06 04:00:00 EDT 2019 · Nature Metabolism

DOI:https://doi.org/10.1038/s42255-019-0061-8· OSTI ID:1559275

Dirice, Ercument ^[1]; Kahraman, Sevim ^[2]; De Jesus, Dario F. ^[2]; El Ouaamari, Abdelfattah ^[1]; Basile, Giorgio ^[3]; Baker, Rocky ^[4]; Yigit, Burcu ^[1]; Piehowski, Paul D. ^[5]; Kim, Mi-Jeong ^[3]; Dwyer, Alex J. ^[6]; Ng, Raymond W. ^[3]; Schuster, Cornelia ^[3]; Vethe, Heidrun ^[3]; Martinov, Tijana ^[6]; Ishikawa, Yuki ^[3]; Teo, Adrian K. ^[3]; Smith, Richard D. ^[5]; Hu, Jiang ^[1]; Haskins, Kathryn ^[4]; Serwold, Thomas ^[3] ; Qian, Weijun ^[5]; Fife, Brian T. ^[6]; Kissler, Stephan ^[3]; Kulkarni, Rohit N. ^[1]

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1. Harvard Medical School
2. Islet Cell & Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School
3. Joslin Diabetes Center
4. University of Colorado
5. BATTELLE (PACIFIC NW LAB)
6. University of Minnesota

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of ß-cells1. Restoration of insulin producing ß-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2-4. Here we report that enhancing ß-cell mass early in life (prior to weaning) results in immunomodulation of T-cells, reduced islet infiltration and lower ß-cell apoptosis, in female NOD mice that together protect them from developing T1D. We observed that a model exhibiting ß-cell hyperplasia on the NOD background (NOD-LIRKO) displayed reduced ß-cell antigens, and islet transplantation studies showed prolonged graft survival of NOD-LIRKO islets even upon exposure to diabetogenic splenocytes in vivo. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented diabetes development in pre-diabetic NOD mice, while conversely; similar protective outcomes were obtained when NOD-LIRKO splenocytes were adoptively transferred after mixing them with diabetogenic NOD splenocytes in a dose-dependent manner. A significant increase in splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population in the NOD-LIRKO mice was observed to drive the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with downregulation of key mediators of cellular function, upregulation of apoptosis and activation of TGF-ß/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill ß-cells. These data provide novel evidence that initiating ß-cell proliferation prior to islet infiltration by immune cells alters the identity of ß-cells, improves pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 1559275
• Report Number(s): PNNL-SA-141695
• Journal Information: Nature Metabolism, Journal Name: Nature Metabolism Journal Issue: 5 Vol. 1
• Country of Publication: United States
• Language: English