| First Author | Zeiser R | Year | 2007 |
| Journal | Blood | Volume | 110 |
| Issue | 13 | Pages | 4588-98 |
| PubMed ID | 17827390 | Mgi Jnum | J:149097 |
| Mgi Id | MGI:3847605 | Doi | 10.1182/blood-2007-08-106005 |
| Citation | Zeiser R, et al. (2007) Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity. Blood 110(13):4588-98 |
| abstractText | 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 of the donor induced a Th-2 cytokine profile in the adoptively transferred T cells and reduced their in vivo expansion, which translated into significantly reduced aGVHD lethality. Host treatment down-regulated costimulatory molecules and MHC class II expression on recipient antigen-presenting cells (APCs) and enhanced the protective statin effect, without impacting graft-versus-leukemia (GVL) activity. The AT effect was partially reversed in STAT6(-/-) donors and abrogated by L-mevalonate, indicating the relevance of STAT6 signaling and the L-mevalonate pathway for AT-mediated aGVHD protection. AT reduced prenylation levels of GTPases, abolished T-bet expression, and increased c-MAF and GATA-3 protein in vivo. Thus, AT has significant protective impact on aGVHD lethality by Th-2 polarization and inhibition of an uncontrolled Th-1 response while maintaining GVL activity, which is of great clinical relevance given the modest toxicity profile of AT. |
