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Haematologica 2018 Volume 104(2):392-402
Stem Cell Transplantation
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
Mélanie Gaignage,1 Reece G. Marillier,1 Perrine M. Cochez,1 Laure Dumoutier,1 Catherine Uyttenhove,1,2 Jean-Paul Coutelier1 and Jacques Van Snick1,2
1de Duve Institute, Université Catholique de Louvain and 2Ludwig Cancer Research, Brussels, Belgium
ABSTRACT
In spite of considerable therapeutic progress, acute graft-versus-host dis- ease still limits allogeneic hematopoietic cell transplantation. We recent- ly 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 pharma- cological TLR7 ligand, R848, in this model and observed complete survival if donor and recipients were treated before transplantation. Mixed lym- phocyte culture performed 48 h after R848-treatment of normal mice demonstrated that both T-cell allo-responsiveness and antigen presenta- tion by CD11b+ and CD8α+ dendritic cells were inhibited. These inhibi- tions were dependent on IFNAR-1 signaling. In the B6 to B6D2F1 trans- plantation 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 inhi- bition 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-versus-host dis- ease and offers potential for safe allogeneic bone marrow transplantation that can be further optimized by inhibition of interleukin-27.
Introduction
Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic option for a wide range of malignant and non-malignant disorders, including acquired and genetic anomalies.1-3 However, it remains plagued by bone marrow failure or graft-versus-host disease (GvHD), which develop in approximately 50% of allogeneic HCT recipients.4 With a death rate in the range of 15%,5 acute GvHD thus remains a major medical challenge, especially in older patients and in steroid-resistant individu- als in whom mortality reaches 90%.6
A hallmark of acute GvHD is the release of inflammatory cytokines and a pathogen- ic contribution has been demonstrated for tumor necrosis factor-alpha (TNFα),7 inter- leukin(IL)-6,8 IL-239 and more recently IL-27.10,11 This last, a member of the IL-6 and IL- 12 families, is a cytokine with multiple activities12 that both promotes Th1 type immune reactions13 and restrains excessive inflammation.14 IL-27 is formed by non- covalently linked p28 (also called IL-30)15 and Epstein-Barr virus-induced gene 3 prod- uct (EBI3), which are structurally related to IL-12p35 and IL-12p40, respectively.13 IL-27
Correspondence:
jacques.vansnick@bru.licr.org
Received: April 12, 2018.
Accepted: September 7, 2018. Pre-published: September 13, 2018.
doi:10.3324/haematol.2018.195628
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/392
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