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

Abstract

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/SMAD3more » 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.« less

Authors:

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];

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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];

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Hu, Jiang ^[1]; Haskins, Kathryn ^[4]; Serwold, Thomas ^[3] more »; Qian, Weijun  ^[5];

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• Search OSTI.GOV for ORCID "0000-0002-5393-2827"
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Fife, Brian T. ^[6]; Kissler, Stephan ^[3]; Kulkarni, Rohit N. ^[1] « less

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+ Show Author Affiliations

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

Publication Date:

2019-05-06

Research Org.:

Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

1559275

Report Number(s):

PNNL-SA-141695

DOE Contract Number:  

AC05-76RL01830

Resource Type:

Journal Article

Journal Name:

Nature Metabolism

Additional Journal Information:

Journal Volume: 1; Journal Issue: 5

Country of Publication:

United States

Language:

English