Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain; Neuromuscular Diseases Group, Sant Pau Biomedical Research Institute, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
Immunology Department, Germans Trias I Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
J Autoimmun. 2024 May;145:103196. doi: 10.1016/j.jaut.2024.103196. Epub 2024 Mar 8.
Type 1 diabetes (T1D) results from a breakdown in immunological tolerance, with pivotal involvement of antigen-presenting cells. In this context, antigen-specific immunotherapies have been developed to arrest autoimmunity, such as phosphatidylserine (PS)-liposomes. However, the role of certain antigen-presenting cells in immunotherapy, particularly human macrophages (Mφ) in T1D remains elusive. The aim of this study was to determine the role of Mφ in antigen-specific immune tolerance and T1D. To that end, we evaluated Mφ ability to capture apoptotic-body mimicking PS-liposomes in mice and conducted a phenotypic and functional characterisation of four human monocyte-derived Mφ (MoMφ) subpopulations (M0, M1, M2a and M2c) after PS-liposomes uptake. Our findings in mice identified Mφ as the most phagocytic cell subset in the spleen and liver. In humans, while phagocytosis rates were comparable between T1D and control individuals, PS-liposome capture dynamics differed among Mφ subtypes, favouring inflammatory (M1) and deactivated (M2c) Mφ. Notably, high nanoparticle concentrations did not affect macrophage viability. PS-liposome uptake by Mφ induced alterations in membrane molecule expression related to immunoregulation, reduced secretion of IL-6 and IL-12, and diminished autologous T-cell proliferation in the context of autoantigen stimulation. These results underscore the tolerogenic effects of PS-liposomes and emphasize their potential to target human Mφ, providing valuable insights into the mechanism of action of this preclinical immunotherapy.
1 型糖尿病（T1D）是由于免疫耐受的破坏，抗原呈递细胞起关键作用。在这种情况下，已经开发了针对抗原的免疫疗法来阻止自身免疫，如磷脂酰丝氨酸（PS）-脂质体。然而，某些抗原呈递细胞在免疫疗法中的作用，特别是 T1D 中的人类巨噬细胞（Mφ），仍然难以捉摸。本研究旨在确定 Mφ 在抗原特异性免疫耐受和 T1D 中的作用。为此，我们评估了 Mφ 捕获模拟 PS-脂质体的凋亡体的能力，并对四种人单核细胞衍生的 Mφ（MoMφ）亚群（M0、M1、M2a 和 M2c）在摄取 PS-脂质体后进行了表型和功能特征分析。我们在小鼠中的研究结果确定了 Mφ 是脾脏和肝脏中最具吞噬能力的细胞亚群。在人类中，虽然 T1D 和对照组个体之间的吞噬率相当，但 PS-脂质体捕获动力学在 Mφ 亚型之间存在差异，有利于炎症（M1）和失活（M2c）Mφ。值得注意的是，高浓度的纳米颗粒不会影响巨噬细胞的活力。Mφ 摄取 PS-脂质体诱导与免疫调节相关的膜分子表达改变，减少 IL-6 和 IL-12 的分泌，并在自身抗原刺激的情况下减弱自身 T 细胞的增殖。这些结果强调了 PS-脂质体的耐受性作用，并强调了它们靶向人类 Mφ 的潜力，为这种临床前免疫疗法的作用机制提供了有价值的见解。
