Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice

被引:17
作者
Grievink, Hendrika W. [1 ,2 ]
Smit, Virginia [1 ]
Verwilligen, Robin A. F. [1 ]
Kleijn, Mireia N. A. Bernabe [1 ]
Smeets, Diede [3 ]
Binder, Christoph J. [3 ]
Yagita, Hideo [4 ]
Moerland, Matthijs [2 ,5 ]
Kuiper, Johan [1 ]
Bot, Ilze [1 ]
Foks, Amanda C. [1 ]
机构
[1] Leiden Univ, Leiden Acad Ctr Drug Res LACDR, Div BioTherapeut, Leiden, Netherlands
[2] Ctr Human Drug Res, Leiden, Netherlands
[3] Med Univ Vienna, Dept Lab Med, Vienna, Austria
[4] Juntendo Univ, Dept Immunol, Tokyo, Japan
[5] Leiden Univ, Dept Clin Pharm & Toxicol, Med Ctr, Leiden, Netherlands
来源
FRONTIERS IN CARDIOVASCULAR MEDICINE | 2021年 / 8卷
关键词
atherosclerosis; immunology; T cells; coinhibitory pathways; immunotherapy; LOW-DENSITY-LIPOPROTEIN; REGULATORY T-CELLS; B-CELLS; PD-1/PD-L1; PATHWAY; INTERFERON-GAMMA; INFLAMMATION; INTERLEUKIN-10; EXPRESSION; ANTIGEN; REGRESSION;
D O I
10.3389/fcvm.2021.740531
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aim: Signaling through the coinhibitory programmed death (PD)-1/PD-L1 pathway regulates T cell responses and can inhibit ongoing immune responses. Inflammation is a key process in the development of atherosclerosis, the underlying cause for the majority of cardiovascular diseases. Dampening the excessive immune response that occurs during atherosclerosis progression by promoting PD-1/PD-L1 signaling may have a high therapeutic potential to limit disease burden. In this study we therefore aimed to assess whether an agonistic PD-1 antibody can diminish atherosclerosis development.Methods and Results: Ldlr(-/-) mice were fed a western-type diet (WTD) while receiving 100 mu g of an agonistic PD-1 antibody or control vehicle twice a week. Stimulation of the PD-1 pathway delayed the WTD-induced monocyte increase in the circulation up to 3 weeks and reduced T cell activation and proliferation. CD4(+) T cell numbers in the atherosclerotic plaque were reduced upon PD-1 treatment. More specifically, we observed a 23% decrease in atherogenic IFN gamma-producing splenic CD4(+) T cells and a 20% decrease in cytotoxic CD8(+) T cells, whereas atheroprotective IL-10 producing CD4(+) T cells were increased with 47%. Furthermore, we found an increase in regulatory B cells, B1 cells and associated atheroprotective circulating oxLDL-specific IgM levels in agonistic PD-1-treated mice. This dampened immune activation following agonistic PD-1 treatment resulted in reduced atherosclerosis development (p < 0.05).Conclusions: Our data show that stimulation of the coinhibitory PD-1 pathway inhibits atherosclerosis development by modulation of T- and B cell responses. These data support stimulation of coinhibitory pathways as a potential therapeutic strategy to combat atherosclerosis.
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页数:12
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