Reversal of new-onset type 1 diabetes with an agonistic TLR4/MD-2 monoclonal antibody

Kyle J. Bednar, Hiroki Tsukamoto, Kritika Kachapati, Shoichiro Ohta, Yuehong Wu, Jonathan D. Katz, Dana P. Ascherman, William M. Ridgway

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Type 1 diabetes (T1D) is currently an incurable disease, characterized by a silent prodromal phase followed by an acute clinical phase, reflecting progressive autoimmune destruction of insulin-producing pancreatic β-cells. Autoreactive T cells play a major role in β-cell destruction, but innate immune cell cytokines and costimulatory molecules critically affect T-cell functional status. We show that an agonistic monoclonal antibody to TLR4/MD-2 (TLR4-Ab) reverses new-onset diabetes in a high percentage of NOD mice. TLR4-Ab induces antigen-presenting cell (APC) tolerance in vitro and in vivo, resulting in an altered cytokine profile, decreased costimulatory molecule expression, and decreased T-cell proliferation in APC:T-cell assays. TLR4-Ab treatment increases T-regulatory cell (Treg) numbers in both the periphery and the pancreatic islet, predominantly expanding the Helios+Nrp-1+Foxp3+ Treg subset. TLR4-Ab treatment in the absence of B cells in NOD.scid mice prevents subsequent T cell-mediated disease, further suggesting a major role for APC tolerization in disease protection. Specific stimulation of the innate immune system through TLR4/MD-2, therefore, can restore tolerance in the aberrant adaptive immune system and reverse new-onset T1D, suggesting a novel immunological approach to treatment of T1D in humans.

Original languageEnglish
Pages (from-to)3614-3626
Number of pages13
JournalDiabetes
Volume64
Issue number10
DOIs
Publication statusPublished - 2015 Oct

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Bednar, K. J., Tsukamoto, H., Kachapati, K., Ohta, S., Wu, Y., Katz, J. D., Ascherman, D. P., & Ridgway, W. M. (2015). Reversal of new-onset type 1 diabetes with an agonistic TLR4/MD-2 monoclonal antibody. Diabetes, 64(10), 3614-3626. https://doi.org/10.2337/db14-1868