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 P Caturegli, Karl L. Womer, Yanfei Huang, Chunfa Jie, Shukti Chakravarti, Jonathan P Schneck, Hideo Yagita, Abdel R Hamad

Research output: Contribution to journalArticle

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

Fingerprint

Inbred NOD Mouse
Fas Ligand Protein
Interleukin-10
Type 1 Diabetes Mellitus
Mutation
T-Lymphocytes
Pancreas
Monoclonal Antibodies
Insulin
Disease Resistance
Neutralizing Antibodies
Autoimmune Diseases
Homeostasis
B-Lymphocytes
Lymph Nodes
Alleles
Maintenance
Injections
Therapeutics
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Inhibition of fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development. / Xiao, Zuoxiang; Mohamood, Abdiaziz S.; Uddin, Sophia; Gutfreund, Rachel; Nakata, Chiaki; Marshall, Andrew; Kimura, Hiroaki; Caturegli, Patrizio P; Womer, Karl L.; Huang, Yanfei; Jie, Chunfa; Chakravarti, Shukti; Schneck, Jonathan P; Yagita, Hideo; Hamad, Abdel R.

In: American Journal of Pathology, Vol. 179, No. 2, 08.2011, p. 725-732.

Research output: Contribution to journalArticle

Xiao, Z, Mohamood, AS, Uddin, S, Gutfreund, R, Nakata, C, Marshall, A, Kimura, H, Caturegli, PP, Womer, KL, Huang, Y, Jie, C, Chakravarti, S, Schneck, JP, Yagita, H & Hamad, AR 2011, 'Inhibition of fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development', American Journal of Pathology, vol. 179, no. 2, pp. 725-732. https://doi.org/10.1016/j.ajpath.2011.04.016
Xiao, Zuoxiang ; Mohamood, Abdiaziz S. ; Uddin, Sophia ; Gutfreund, Rachel ; Nakata, Chiaki ; Marshall, Andrew ; Kimura, Hiroaki ; Caturegli, Patrizio P ; Womer, Karl L. ; Huang, Yanfei ; Jie, Chunfa ; Chakravarti, Shukti ; Schneck, Jonathan P ; Yagita, Hideo ; Hamad, Abdel R. / Inhibition of fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development. In: American Journal of Pathology. 2011 ; Vol. 179, No. 2. pp. 725-732.
@article{b5b5a75dfece4728821cd95bcbf59874,
title = "Inhibition of fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development",
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.",
author = "Zuoxiang Xiao and Mohamood, {Abdiaziz S.} and Sophia Uddin and Rachel Gutfreund and Chiaki Nakata and Andrew Marshall and Hiroaki Kimura and Caturegli, {Patrizio P} and Womer, {Karl L.} and Yanfei Huang and Chunfa Jie and Shukti Chakravarti and Schneck, {Jonathan P} and Hideo Yagita and Hamad, {Abdel R}",
year = "2011",
month = "8",
doi = "10.1016/j.ajpath.2011.04.016",
language = "English (US)",
volume = "179",
pages = "725--732",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Inhibition of fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development

AU - Xiao, Zuoxiang

AU - Mohamood, Abdiaziz S.

AU - Uddin, Sophia

AU - Gutfreund, Rachel

AU - Nakata, Chiaki

AU - Marshall, Andrew

AU - Kimura, Hiroaki

AU - Caturegli, Patrizio P

AU - Womer, Karl L.

AU - Huang, Yanfei

AU - Jie, Chunfa

AU - Chakravarti, Shukti

AU - Schneck, Jonathan P

AU - Yagita, Hideo

AU - Hamad, Abdel R

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80052501666&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052501666&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2011.04.016

DO - 10.1016/j.ajpath.2011.04.016

M3 - Article

C2 - 21718680

AN - SCOPUS:80052501666

VL - 179

SP - 725

EP - 732

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 2

ER -