Committee on Immunology, University of Chicago, Chicago, IL, USA.
Pritzker School for Molecular Engineering, University of Chicago, Chicago, IL, USA.
Nat Biomed Eng. 2023 Sep;7(9):1142-1155. doi: 10.1038/s41551-023-01086-2. Epub 2023 Sep 7.
Inducing antigen-specific tolerance during an established immune response typically requires non-specific immunosuppressive signalling molecules. Hence, standard treatments for autoimmunity trigger global immunosuppression. Here we show that established antigen-specific responses in effector T cells and memory T cells can be suppressed by a polymer glycosylated with N-acetylgalactosamine (pGal) and conjugated to the antigen via a self-immolative linker that allows for the dissociation of the antigen on endocytosis and its presentation in the immunoregulatory environment. We show that pGal-antigen therapy induces antigen-specific tolerance in a mouse model of experimental autoimmune encephalomyelitis (with programmed cell-death-1 and the co-inhibitory ligand CD276 driving the tolerogenic responses), as well as the suppression of antigen-specific responses to vaccination against a DNA-based simian immunodeficiency virus in non-human primates. Our findings show that pGal-antigen therapy invokes mechanisms of immune tolerance to resolve antigen-specific inflammatory T-cell responses and suggest that the therapy may be applicable across autoimmune diseases.
在已建立的免疫反应中诱导抗原特异性耐受通常需要非特异性免疫抑制信号分子。因此，自身免疫的标准治疗会引发全身性免疫抑制。在这里，我们表明，通过与通过自毁性连接子与抗原连接的 N-乙酰半乳糖胺（pGal）糖基化的聚合物，可以抑制效应 T 细胞和记忆 T 细胞中已建立的抗原特异性反应，该连接子允许在细胞内吞作用下抗原解离，并在免疫调节环境中呈递抗原。我们表明，pGal-抗原治疗可在实验性自身免疫性脑脊髓炎的小鼠模型中诱导抗原特异性耐受（程序性细胞死亡-1 和共抑制配体 CD276 驱动耐受反应），以及抑制针对基于 DNA 的猴免疫缺陷病毒的疫苗接种引起的抗原特异性反应。我们的发现表明，pGal-抗原治疗引发了免疫耐受机制，以解决抗原特异性炎症性 T 细胞反应，并表明该疗法可能适用于各种自身免疫性疾病。
