Type 1 Diabetes: Involvement of Extracellular Matrix in Immune-Mediated Pancreatic Islet Destruction

• Applicant: Dr. Nadine Nagy
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213790947

• Final Report Year: 2015

Final Report Abstract

We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) characterize autoimmune insulitis in human type 1 diabetes (T1D) but the significance of these deposits was unclear. Here, we demonstrate that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA (DORmO) mouse model of T1D, we show that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. 4- MU reduced HA accumulation, constrained effector T-cells to non-destructive insulitis, and increased numbers of intra-islet Foxp3+ regulatory T-cells (Treg). Consistent with this, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.

Publications

• Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. Blood. 2012 Jun 14;119(24):5931-42
  Meinecke AK, Nagy N, Lago GD, Kirmse S, Klose R, Schrödter K, Zimmermann A, Helfrich I, Rundqvist H, Theegarten D, Anhenn O, Orian-Rousseau V, Johnson RS, Alitalo K, Fischer JW, Fandrey J, Stockmann C
  
• Type 1 Diabetes: Involvement of Extracellular Matrix in Immune-Mediated Pancreatic Islet Destruction. Abstract book, American Society for Biochemistry and Molecular Biology (ASBMB) meeting 11-2012 San Diego
  Nagy N, Kaber G, Campbell DJ, Wight TN
  
• . Inhibitory role of the small leucine-rich proteoglycan biglycan in bladder cancer. PLoS One. 2013 Nov 6;8(11):e80084
  Niedworok C, Roeck K, Kretschmer I, Freudenberger T, Nagy N, Szarvas T, Vom Dorp F, Reis H, Ruebben H, Fischer JW
  
• Involvement of Hyaluronan and Related Extracellular Matrix Molecules in Immune-Mediated Pancreatic Islet Destruction. Abstract book, Keystone meeting 04-2013 Whistler
  Nagy N, Kaber G, Campbell DJ, Bollyky PL, Wight TN
  
• Type 1 Diabetes: Involvement of Hyaluronan and Related Extracellular Matrix Molecules in Immune-Mediated Pancreatic Islet Destruction. Abstract book, International Society for Hyaluronan Sciences (ISHAS) meeting 06-2013 Oklahoma City
  Nagy N, Kaber G, Campbell DJ, Day AJ, Bollyky PL, Wight TN
  
• Hyaluronan and hyaluronanbinding proteins accumulate in both human type 1 diabetic islets and lymphoid tissues and associate with inflammatory cells in insulitis. Diabetes. 2014 Aug; 63(8):2727-43
  Bogdani M, Johnson PY, Potter-Perigo S, Nagy N, Day AJ, Bollyky PL, Wight TN
  
• Hyaluronan is Crucial for Autoimmune Diabetes Development and Progression. Abstract book, American Society for Matric Biology (ASMB) meeting 10-2014 Cleveland
  Nagy N, Kaber G, Johnson PY, Campbell DJ, Gebe JA, Day AJ, Wight TN, Bollyky PL
  
• 4-Methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Frontiers in Immunology Front. Immunol. 6:123, 23 March 2015
  Nagy N, Kuipers HF, Frymoyer AR, Ishak HD, Bollyky JB, Wight TN, Bollyky PL
  
• Hyaluronan: A Mediator of Islet Dysfunction and Destruction in Diabetes? Journal of Histochemistry & Cytochemistry, Volume: 63 issue: 8, page(s): 592-603, Issue published: August 1, 2015
  Hull RL, Bogdani M, Nagy N, Johnson PY, Wight TN
  
• Inhibition of Hyaluronan Synthesis Restores Immune Tolerance During Autoimmune Insulitis. Journal of Clinical Investigation J Clin Invest. 2015;125(10):3928–3940
  Nagy N, Kaber G, Johnson PY, Gebe JA, Preisinger A, Falk B, Sunkari VG, Gooden MD, Vernon RB, Bogdani M, Kuipers HF, Day AJ, Campbell DJ, Wight TN, Bollyky PL
  
• The detection of glycosaminoglycans in pancreatic islets and lymphoid tissues. Methods Mol Biol. 2015;1229:413-30
  Bogdani M, Simeonovic C, Nagy N, Johnson PY, Chan CK, Wight TN