Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA 94305, United States.
Division of Blood and Marrow Transplantation, Dept. of Medicine, Stanford University School of Medicine, CCSR, 1291 Welch Road, Stanford, CA 94305, United States.
Matrix Biol. 2021 Feb;96:69-86. doi: 10.1016/j.matbio.2020.12.001. Epub 2020 Dec 5.
A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition of de novo antigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.
细胞周透明质酸聚糖层环绕着成熟树突状细胞（DC），并有助于细胞间的相互作用。我们想知道 4-甲基伞形酮（4MU），一种透明质酸合成的口服抑制剂，是否可以抑制抗原呈递。我们发现 4MU 处理可减少细胞周透明质酸聚糖，破坏 DC 与 T 细胞之间的相互作用，并防止体外和体内 T 细胞增殖。这些效应仅在 4MU 在初始抗原呈递之前添加而不是之后添加时观察到，与 4MU 介导的新抗原反应抑制一致。基于这些发现，我们发现 4MU 可延迟小鼠同种异体胰岛移植和同种异体心脏移植的排斥反应，并抑制人混合淋巴细胞反应中的同种异体 T 细胞活化。我们得出结论，4MU 是一种已批准的药物，可能作为辅助剂具有延迟移植排斥反应的益处。
