GVHD is a host tissue injury mediated by donor-host immune reactions, and a major complication in allogeneic hematopoietic stem cell transplantation. Peroxisome proliferator-activated receptor-α (PPARδ) plays an important role in regulating immune responses. We investigated the role of rosiglitazone, a synthetic PPARδ agonist, in a murine parent-to-F1 GVHD model. During mixed lymphocyte reactions (MLR), rosiglitazone inhibited the proliferative response and cytotoxicity of responder cells, and induced more apoptosis in CD4+, CD8+, and B220+ cells than in NK1.1+, Mac-1+, CD4/CD25+ and CD3/NK1.1+ cells. The in vivo administration of rosiglitazone demonstrated histologic improvements of GVHD in the liver, skin, spleen and intestine. Rosiglitazone treatment inhibited GVHD-induced increases in serum levels of TNFα, IFNα, IL-6, and IL-12, and the decreases in TGFβ and IL-10. Splenic leukocyte immunophenotyping demonstrated that while the proportions of both donor and host CD4/CD25+ and CD3/NK1.1+ cells were increased by the treatment with rosiglitazone, both donor and host CD8+ cells were decreased. Rosiglitazone treatment inhibited GVHD-induced decreases in the expression of phosphate and tensin homologue deleted on chromosome ten (PTEN), and the increases in the expression of p-Akt and nuclear NF-κB in the spleen. These results indicate that rosiglitazone and activation of PPARδ may be useful to protect the host from GVHD.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4413. doi:1538-7445.AM2012-4413