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 NOD-wild-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 receptor-blocking 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.
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Zuoxiang
authors: Z
authors: Xiao
authors: Abdiaziz S
authors: AS
authors: Mohamood
authors: Sophia
authors: S
authors: Uddin
authors: Rachel
authors: R
authors: Gutfreund
authors: Chiaki
authors: C
authors: Nakata
authors: Andrew
authors: A
authors: Marshall
authors: Hiroaki
authors: H
authors: Kimura
authors: Patrizio
authors: P
authors: Caturegli
authors: Karl L
authors: KL
authors: Womer
authors: Yanfei
authors: Y
authors: Huang
authors: Chunfa
authors: C
authors: Jie
authors: Shukti
authors: S
authors: Chakravarti
authors: Jonathan P
authors: JP
authors: Schneck
authors: Hideo
authors: H
authors: Yagita
authors: Abdel Rahim A
authors: AR
authors: Hamad
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006720:Homozygote; D007107:Immune System; D007328:Insulin / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009154:Mutation; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D053222:Fas Ligand Protein; D007328:Insulin; D016753:Interleukin-10