Inhibition of fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development

Zuoxiang Xiao, Abdiaziz S. Mohamood, Sophia Uddin, Rachel Gutfreund, Chiaki Nakata, Andrew Marshall, Hiroaki Kimura, Patrizio Caturegli, Karl L. Womer, Yanfei Huang, Chunfa Jie, Shukti Chakravarti, Jonathan P. Schneck, Hideo Yagita, Abdel Rahim A. Hamad

Research output: Contribution to journalArticlepeer-review

Abstract

Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of pancreatic insulin-producing β cells by autoreactive T cells early in life. Despite daily insulin injections, patients typically develop cardiovascular and other complications; and intensive efforts are being directed toward identifying therapeutic targets to prevent the disease without directly impinging on the host defense. Fas ligand (FasL) is one potential target. Fas-FasL interactions primarily regulate T-cell homeostasis, not activation. Nevertheless, spontaneous gene mutation of Fas (called lpr mutation) or FasL (called the gld mutation) prevents autoimmune diabetes in nonobese diabetic (NOD) mice, the widely used model for T1D. Furthermore, although homozygous gld mutations cause age-dependent lymphoproliferation, limiting the gld mutation to one allele (NOD-gld/+) or treating NODwild-type mice with FasL-neutralizing monoclonal antibody completely prevents the disease development without causing lymphoproliferation or immune suppression. Herein, we show that the heterozygous gld mutation inhibits the accumulation of diabetogenic T cells in the pancreas, without interfering with their proliferation and expansion in the draining pancreatic lymph nodes. Pancreata from NOD-gld/+ mice contained B cells that expressed CD5 and produced IL-10, which was critical for maintenance of the disease resistance because its neutralization with an IL-10 receptorblocking monoclonal antibody allowed accumulation of CD4 T cells in the pancreas and led to insulitis development. The results provide novel insights into the pathogenesis of T1D that could have important therapeutic implications.

Original languageEnglish (US)
Pages (from-to)725-732
Number of pages8
JournalAmerican Journal of Pathology
Volume179
Issue number2
DOIs
StatePublished - Aug 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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