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.

中文翻译：

---

使用富含磷脂酰丝氨酸的脂质体靶向巨噬细胞作为 1 型糖尿病的潜在抗原特异性免疫疗法

1 型糖尿病 (T1D) 是免疫耐受破坏的结果，其中抗原呈递细胞起着关键作用。在这种情况下，已经开发出抗原特异性免疫疗法来阻止自身免疫，例如磷脂酰丝氨酸（PS）脂质体。然而，某些抗原呈递细胞在免疫治疗中的作用，特别是人类巨噬细胞 (Mφ) 在 T1D 中的作用仍然难以捉摸。本研究的目的是确定 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 在小鼠中捕获模拟凋亡体 PS 脂质体的能力，并对 PS 脂质体后四种人单核细胞来源的 Mφ (MoMφ) 亚群（M0、M1、M2a 和 M2c）进行了表型和功能表征吸收。我们在小鼠身上的研究结果表明，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 和对照个体之间的吞噬率相当，但 Mφ 亚型之间的 PS 脂质体捕获动力学不同，有利于炎症 (M1) 和失活 (M2c) Mφ。值得注意的是，高纳米颗粒浓度并不影响巨噬细胞的活力。Mφ对PS脂质体的摄取诱导了与免疫调节相关的膜分子表达的改变，减少了IL-6和IL-12的分泌，并在自身抗原刺激的情况下减少了自体T细胞的增殖。这些结果强调了 PS 脂质体的耐受作用，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。