Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Topas Therapeutics GmbH, Hamburg, Germany.
Immunology. 2021 Apr;162(4):452-463. doi: 10.1111/imm.13298. Epub 2021 Jan 7.
Autoimmune diseases are caused by adaptive immune responses to self-antigens. The development of antigen-specific therapies that suppress disease-related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC-targeting nanoparticles provides effective protection from CD4 T-cell-driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen-specific treatment of a CD8 T-cell-driven autoimmune disease. As a model for CD8 T-cell-mediated autoimmunity, we used OT-1 T-cell-driven cholangitis in K14-OVAp mice expressing the cognate MHC I-restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide-conjugated nanoparticles were administered intravenously one day before transfer of OT-1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide-conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross-presented the delivered peptide on MHC I molecules. Intriguingly, K14-OVAp mice receiving SIINFEKL-loaded nanoparticles manifested significantly reduced liver damage compared with vehicle-treated K14-OVAp mice. Mechanistically, treatment with LSEC-targeting SIINFEKL-loaded nanoparticles significantly reduced the number of liver-infiltrating OT-1 T cells, which up-regulated expression of the co-inhibitory receptor PD-1 and down-regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross-present nanoparticle-bound peptides on MHC I molecules. Therefore, nanoparticle-mediated autoantigen peptide delivery to LSECs might serve the antigen-specific treatment of CD8 T-cell-driven autoimmune disease.
自身免疫性疾病是由适应性免疫应答自身抗原引起的。开发针对抗原的治疗方法，抑制与疾病相关但不与非相关免疫反应一般相关的免疫反应，是生物医学研究的一个重要目标。我们之前已经表明，使用针对肝窦内皮细胞（LSEC）的靶向纳米颗粒将髓鞘肽递送至 LSEC 可提供针对 CD4 T 细胞驱动的自身免疫性脑脊髓炎的有效保护。在这里，我们研究了这种方法是否也可用于针对 CD8 T 细胞驱动的自身免疫性疾病的抗原特异性治疗。作为 CD8 T 细胞介导的自身免疫的模型，我们使用 K14-OVAp 小鼠中的 OT-1 T 细胞驱动的胆管炎，该模型在胆管细胞中表达同源 MHC I 限制性 SIINFEKL 肽。为了研究将肽递送至 LSEC 是否可以调节胆管炎，我们在 OT-1 T 细胞转移前一天静脉内给予 SIINFEKL 肽缀合的纳米颗粒；在细胞转移后 5 天，分析肝病理学和肝浸润。SIINFEKL 肽缀合的纳米颗粒在体内被 LSEC 迅速摄取，并有效地在 MHC I 分子上交叉呈递递送至的肽。有趣的是，与用载体处理的 K14-OVAp 小鼠相比，接受负载 SIINFEKL 的纳米颗粒的 K14-OVAp 小鼠的肝损伤明显减轻。从机制上讲，用 LSEC 靶向的负载 SIINFEKL 的纳米颗粒治疗可显著减少肝浸润的 OT-1 T 细胞的数量，这上调了共抑制受体 PD-1 的表达，并下调了细胞毒性效应功能和炎性细胞因子的产生。这些发现表明，耐受的 LSEC 可以有效地内化循环纳米颗粒，并在 MHC I 分子上交叉呈递纳米颗粒结合的肽。因此，纳米颗粒介导的自身抗原肽递送至 LSEC 可能用于针对 CD8 T 细胞驱动的自身免疫性疾病的抗原特异性治疗。
