TLR7 ligand R848 prevents mouse graft-versus-host disease and cooperates with anti-IL-27 antibody for maximal protection and Treg upregulation.

TLR7 ligand R848 prevents mouse graft-versus-host disease and cooperates with anti-IL-27 antibody for maximal protection and Treg upregulation. Haematologica. 2018 Sep 13;: Authors: Gaignage M, Marillier RG, Cochez PM, Dumoutier L, Uyttenhove C, Coutelier JP, Van Snick J Abstract In spite of considerable therapeutic progress, acute graft-versus-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 pharmacologic 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 IFNγ, TNFα and IL-27 while upregulating active TGF-β1 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 irr...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research