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Citations to this article

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Published September 14, 2015
Citation Information: J Clin Invest. 2015;125(10):3928-3940. https://doi.org/10.1172/JCI79271.
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Research Article Immunology Article has an altmetric score of 136

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

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Abstract

We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined 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. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, 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.

Authors

Nadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, Paul L. Bollyky

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Total citations by year

Year: 2024 2023 2022 2021 2020 2019 2018 2017 2016 Total
Citations: 6 6 5 9 7 6 6 3 5 53
Citation information
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Citations to this article in year 2020 (7)

Title and authors Publication Year
High Molecular Weight Hyaluronan Attenuates Tubulointerstitial Scarring in Kidney Injury
Xinyi Wang, Swathi Balaji, Emily H. Steen, Alexander J. Blum, Hui Li, Christina K. Chan, Scott R. Manson, Thomas C. Lu, Meredith M. Rae, Paul F. Austin, Thomas N. Wight, Paul L. Bollyky, Jizhong Cheng, Sundeep G. Keswani
JCI Insight 2020
Characteristics of Hyaluronan Synthesis Inhibition by 4-Methylumbelliferone in Orbital Fibroblasts
E Galgoczi, F Jeney, M Katko, A Erdei, A Gazdag, L Sira, M Bodor, E Berta, B Ujhelyi, Z Steiber, F Gyory, EV Nagy
Investigative ophthalmology & visual science 2020
The Heparan Sulfate Mimetic PG545 Modulates T Cell Responses and Prevents Delayed-Type Hypersensitivity
IO Koliesnik, HF Kuipers, CO Medina, S Zihsler, D Liu, JD Belleghem, PL Bollyky
Frontiers in immunology 2020
The liver fibrosis niche: Novel insights into the interplay between fibrosis-composing mesenchymal cells, immune cells, endothelial cells, and extracellular matrix
M Matsuda, E Seki
Food and Chemical Toxicology 2020
Weekly injection of IL-2 using an injectable hydrogel reduces autoimmune diabetes incidence in NOD mice
N Nagy, G Kaber, MJ Kratochvil, HF Kuipers, SM Ruppert, K Yadava, J Yang, SC Heilshorn, SA Long, A Pugliese, PL Bollyky
Diabetologia 2020
The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology
M S., J Melrose, AJ Day, JM Whitelock
Journal of Histochemistry & Cytochemistry 2020
Synucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling
FN Soria, C Paviolo, E Doudnikoff, ML Arotcarena, A Lee, N Danné, AK Mandal, P Gosset, B Dehay, L Groc, L Cognet, E Bezard
Nature Communications 2020

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