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

Hendrika W Grievink,Johan Kuiper,Matthijs Moerland,Ilze Bot,Hideo Yagita,Christoph J Binder,Virginia Smit,Amanda C Foks,Robin A F Verwilligen,Diede Smeets,Mireia N A Bernabé Kleijn

doi:10.3389/fcvm.2021.740531

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.

Highlights

Atherosclerosis is a chronic autoimmune disease characterized by the accumulation of lipids and immune cells, such as macrophages and pro-atherogenic IFNγ-producing Th1 cells, in the atherosclerotic plaque [1, 2]
Immune cells respond to atherosclerosis-specific antigens, such as apoB100, the primary protein in low-density lipoprotein (LDL), which are presented via MHC molecules on the surface of antigen-presenting cells (APCs)
To assess the short-term effects of programmed death (PD)-1 stimulation on the immune system, Ldlr−/− mice were treated for 2 weeks with a PD-1 agonist or control vehicle while receiving a western-type diet (WTD) diet

Summary

Introduction

Atherosclerosis is a chronic autoimmune disease characterized by the accumulation of lipids and immune cells, such as macrophages and pro-atherogenic IFNγ-producing Th1 cells, in the atherosclerotic plaque [1, 2]. Subsequent activation of immune cells is regulated by a network of costimulatory and coinhibitory molecules present on both T cells and APCs. The most familiar costimulatory network is the B7/CD28 family, which has proven to be detrimental for Th1-driven atherosclerosis [3]. In the past two decades, interference in other costimulatory networks, including the CD40-CD40L and OX40-OX40L pathways, confirmed its potential to inhibit experimental atherosclerosis and to target a broad range of immune responses involved in this disease process [4, 5]. It has been shown that the PD-1/PD-L1 pathway is a key regulator of many autoimmune diseases, including rheumatoid arthritis [13], multiple sclerosis [14], and cardiac inflammation [15]

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