The TLR7 ligand R848 prevents mouse graft- versus -host disease and cooperates with anti-interleukin-27 antibody for maximal protection and regulatory T-cell upregulation

• Published in: Haematologica (Roma) Vol. 104; no. 2; pp. 392 - 402
• Main Authors: Gaignage, Mélanie, Marillier, Reece G, Cochez, Perrine M, Dumoutier, Laure, Uyttenhove, Catherine, Coutelier, Jean-Paul, Van Snick, Jacques
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.02.2019
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Graft vs Host Disease - etiology; Graft vs Host Disease - mortality; Graft vs Host Disease - prevention & control; Imidazoles - pharmacology; Immunomodulation - drug effects; Interleukin-27 - antagonists & inhibitors; Ligands; Melanoma, Experimental; Mice; Neoplasm Transplantation; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Toll-Like Receptor 7 - metabolism
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2018.195628

In spite of considerable therapeutic progress, acute graft- -host disease still limits allogeneic hematopoietic cell transplantation. We recently reported that mouse infection with nidovirus lactate dehydrogenase elevating virus impairs disease in non-conditioned B6D2F1 recipients of parental B6 spleen cells. As this virus activates TLR7, we tested a pharmacological TLR7 ligand, R848, in this model and observed complete survival if donor and recipients were treated before transplantation. Mixed lymphocyte culture performed 48 h after R848-treatment of normal mice demonstrated that both T-cell allo-responsiveness and antigen presentation by CD11b and CD8α dendritic cells were inhibited. These inhibitions were dependent on IFNAR-1 signaling. In the B6 to B6D2F1 transplantation model, R848 decelerated, but did not abrogate, donor T-cell implantation and activation. However, it decreased interferon-gamma, tumor necrosis factor-alpha and interleukin-27 while upregulating active transforming growth factor-beta 1 plasma levels. In addition, donor and recipient Foxp3 regulatory T-cell numbers were increased in recipient mice and their elimination compromised disease prevention. R848 also strongly improved survival of lethally irradiated BALB/c recipients of B6 hematopoietic cells and this also correlated with an upregulation of CD4 and CD8 Foxp3 regulatory T cells that could be further increased by inhibition of interleukin-27. The combination of anti-interleukin-27p28 mono -clonal antibody and R848 showed strong synergy in preventing disease in the B6 to B6D2F1 transplantation model when recipients were sublethally irradiated and this also correlated with upregulation of regulatory T cells. We conclude that R848 modulates multiple aspects of graft- -host disease and offers potential for safe allogeneic bone marrow transplantation that can be further optimized by inhibition of interleukin-27.