Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity.

摘要: We investigated whether atorvastatin (AT) was capable of protecting animals from acute graft-versus-host disease (aGVHD) across major histocompatibility complex (MHC) mismatch barriers. AT treatment the donor induced a Th-2 cytokine profile in adoptively transferred T cells and reduced their vivo expansion, which translated into significantly aGVHD lethality. Host down-regulated costimulatory molecules MHC class II expression on recipient antigen-presenting (APCs) enhanced protective statin effect, without impacting graft-versus-leukemia (GVL) activity. The effect partially reversed STAT6−/− donors abrogated by L-mevalonate, indicating relevance STAT6 signaling L-mevalonate pathway for AT-mediated protection. prenylation levels GTPases, abolished T-bet expression, increased c-MAF GATA-3 protein vivo. Thus, has significant impact lethality polarization inhibition an uncontrolled Th-1 response while maintaining GVL activity, is great clinical given modest toxicity AT.