AUTHOR=Grievink Hendrika W. , Smit Virginia , Verwilligen Robin A. F. , Bernabé Kleijn Mireia N. A. , Smeets Diede , Binder Christoph J. , Yagita Hideo , Moerland Matthijs , Kuiper Johan , Bot Ilze , Foks Amanda C.
TITLE=Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice
JOURNAL=Frontiers in Cardiovascular Medicine
VOLUME=8
YEAR=2021
URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.740531
DOI=10.3389/fcvm.2021.740531
ISSN=2297-055X
ABSTRACT=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 μg 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 IFNγ-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.