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.

一层细胞外透明质酸包裹着成熟的树突状细胞 (DC)，并有助于细胞间的相互作用。我们询问 4-甲基伞形酮 (4MU)，一种 HA 合成的口服抑制剂，是否可以抑制抗原呈递。我们发现 4MU 治疗减少了细胞周围的透明质酸，破坏了 DC 和 T 细胞之间的相互作用，并在体外和体内阻止了 T 细胞增殖。仅当在初始抗原呈递之前而不是之后添加 4MU 时才观察到这些效应，这与 4MU 介导的从头抑制一致抗原反应。基于这些发现，我们发现 4MU 可延缓小鼠异基因胰岛移植和异基因心脏移植的排斥反应，并抑制人类混合淋巴细胞反应中的异基因 T 细胞活化。我们得出结论，4MU 是一种获批的药物，作为一种辅助剂可能有助于延缓移植排斥反应。