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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:
 [1];  [2];  [2];  [1];  [3];  [4];  [1]; ORCiD logo [5];  [3];  [6];  [3];  [3];  [3];  [6];  [3];  [3]; ORCiD logo [5];  [1];  [4];  [3] more »; ORCiD logo [5];  [6];  [3];  [1] « less
  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:
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

Citation Formats

Dirice, Ercument, Kahraman, Sevim, De Jesus, Dario F., El Ouaamari, Abdelfattah, Basile, Giorgio, Baker, Rocky, Yigit, Burcu, Piehowski, Paul D., Kim, Mi-Jeong, Dwyer, Alex J., Ng, Raymond W., Schuster, Cornelia, Vethe, Heidrun, Martinov, Tijana, Ishikawa, Yuki, Teo, Adrian K., Smith, Richard D., Hu, Jiang, Haskins, Kathryn, Serwold, Thomas, Qian, Weijun, Fife, Brian T., Kissler, Stephan, and Kulkarni, Rohit N. Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes. United States: N. p., 2019. Web. doi:10.1038/s42255-019-0061-8.
Dirice, Ercument, Kahraman, Sevim, De Jesus, Dario F., El Ouaamari, Abdelfattah, Basile, Giorgio, Baker, Rocky, Yigit, Burcu, Piehowski, Paul D., Kim, Mi-Jeong, Dwyer, Alex J., Ng, Raymond W., Schuster, Cornelia, Vethe, Heidrun, Martinov, Tijana, Ishikawa, Yuki, Teo, Adrian K., Smith, Richard D., Hu, Jiang, Haskins, Kathryn, Serwold, Thomas, Qian, Weijun, Fife, Brian T., Kissler, Stephan, & Kulkarni, Rohit N. Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes. United States. doi:10.1038/s42255-019-0061-8.
Dirice, Ercument, Kahraman, Sevim, De Jesus, Dario F., El Ouaamari, Abdelfattah, Basile, Giorgio, Baker, Rocky, Yigit, Burcu, Piehowski, Paul D., Kim, Mi-Jeong, Dwyer, Alex J., Ng, Raymond W., Schuster, Cornelia, Vethe, Heidrun, Martinov, Tijana, Ishikawa, Yuki, Teo, Adrian K., Smith, Richard D., Hu, Jiang, Haskins, Kathryn, Serwold, Thomas, Qian, Weijun, Fife, Brian T., Kissler, Stephan, and Kulkarni, Rohit N. Mon . "Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes". United States. doi:10.1038/s42255-019-0061-8.
@article{osti_1559275,
title = {Increased ß-cell proliferation before immune cell invasion prevents progression of type 1 diabetes},
author = {Dirice, Ercument and Kahraman, Sevim and De Jesus, Dario F. and El Ouaamari, Abdelfattah and Basile, Giorgio and Baker, Rocky and Yigit, Burcu and Piehowski, Paul D. and Kim, Mi-Jeong and Dwyer, Alex J. and Ng, Raymond W. and Schuster, Cornelia and Vethe, Heidrun and Martinov, Tijana and Ishikawa, Yuki and Teo, Adrian K. and Smith, Richard D. and Hu, Jiang and Haskins, Kathryn and Serwold, Thomas and Qian, Weijun and Fife, Brian T. and Kissler, Stephan and Kulkarni, Rohit N.},
abstractNote = {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.},
doi = {10.1038/s42255-019-0061-8},
journal = {Nature Metabolism},
number = 5,
volume = 1,
place = {United States},
year = {2019},
month = {5}
}

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