Hyaluronan synthesis inhibition impairs antigen presentation and delays transplantation rejection

• Published in: Matrix biology Vol. 96; pp. 69 - 86
• Main Authors: Marshall, Payton L., Nagy, Nadine, Kaber, Gernot, Barlow, Graham L., Ramesh, Amrit, Xie, Bryan J., Linde, Miles H., Haddock, Naomi L., Lester, Colin A., Tran, Quynh-Lam, de Vries, Christiaan R., Hargil, Aviv, Malkovskiy, Andrey V., Gurevich, Irina, Martinez, Hunter A., Kuipers, Hedwich F., Yadava, Koshika, Zhang, Xiangyue, Evanko, Stephen P., Gebe, John A., Wang, Xi, Vernon, Robert B., de la Motte, Carol, Wight, Thomas N., Engleman, Edgar G., Krams, Sheri M., Meyer, Everett H., Bollyky, Paul L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2021; Elsevier Science Ltd
• Subjects: 4-methylumbelliferone; Animals; Antigen presentation; Antigen Presentation - drug effects; Cell activation; Cell interactions; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Disease Models, Animal; Glycocalyx; Graft rejection; Graft Rejection - immunology; Graft Rejection - prevention & control; Heart transplantation; Heart Transplantation - adverse effects; Humans; Hyaluronan; Hyaluronic acid; Hyaluronic Acid - biosynthesis; Hymecromone - administration & dosage; Hymecromone - pharmacology; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes - immunology; Lymphocytes T; Mice; Pancreas transplantation; Pancreas Transplantation - adverse effects; Pancreatic islet transplantation; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; Transplantation; Transplantation, Homologous; Transplants & implants; 4-methylumbelliferone; Antigen presentation; Dendritic cells; Transplantation; IS; Hyaluronan; Glycocalyx; APC; BMDC; HA; PCM; HAS; 4MU; HYAL; DC
• ISSN: 0945-053X; 1569-1802; 1569-1802
• DOI: 10.1016/j.matbio.2020.12.001

•Hyaluronan (HA) is deposited in inflamed lymph nodes by antigen presenting cells.•Inhibition of HA prevents inflammatory T-cell activation and promotes FoxP3+ Tregs.•Treatment with the HA inhibitor 4-methylumbelliferone (4MU) prevents antigen specific T-cell responses.•4MU prolongs time to rejection of organ transplantation. 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.