Targeting danger signaling and APCs. The left panel highlights the central role of danger signals and APC activation during GVHD. Tissue damage induced by the conditioning regimen induces the release of ATP and transit of bacteria/bacterial components, which in turn induces activation of DC (aDC) leading to priming of allo-reactive T cells. The right panel illustrates potential strategies interfering with these processes of APC activation to inhibit or prevent GVHD development. Promising strategies include TLR-inhibition by MyD88-inhibitors (ST825), APC modification by HDACi or TKI or blockade of ATP-signaling by P2X7-inhibitors (A-438079). Moreover, stimulation of APC by MDP might induce a tolerogenic APC-phenotype. Compounds in clinical testing are shown in brown, promising strategies to be tested in the future in humans are given in red. TC indicates T-cell; DC, dendritic cell; aDC, activated DC; Treg, regulatory T-cell; PRR, pattern recognition receptor; TLR, toll-like receptor; HDACi, histone deacetylase inhibitor; TKI, tyrosine kinase inhibitor; NOD/CARD, nucleotidebinding oligomerization domain containing/caspase recruitment domain; tDC, tolerogenic DC; and MDP, muramyl-dipeptide.