Inhibition of Graft-Versus-Host-Disease (GVHD) by Treatment with the Cyclopentenone Prostaglandin 15d-PGJ2 Involves Modulation of the NF-κB Signaling Pathway.

Abstract

Graft-versus-host disease (GVHD) mediated by alloreactive donor T cells is the most dreaded complication after allogeneic bone marrow transplantation (BMT). Interaction of donor T cells with host antigen presenting cells is considered to be central to the development of GVHD. Furthermore, GVHD development depends on the inflammatory response induced by the conditioning regimen. Interfering with inflammatory signaling pathways could be an approach to prevent GVHD without compromising the graft-versus-malignancy reaction. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARγ agonists, such as 15-deoxy -Δ12,14-Prostaglandin J2 (15d-PGJ2) have been shown to have potent immunomodulatory effects on B and T lymphocytes as well as DCs, and recent studies have demonstrated protective effects of PPARγ agonists on animal models of autoimmunity including experimental allergic encephalomyelitis (EAE), asthma, arthritis, colitis and diabetes. There is very few data addressing the role of PPARγ agonists on GVHD. The aim of this study was to investigate the protective effect and mechanism of 15d-PGJ2 on experimental GVHD. GVHD was induced following lethal irradiation (1075 rad) using the fully MHC-mismatched strain combination BALB/c to B6. Recipients were treated with 1 mg/kg of 15d-PGJ2 i.p on days −1, +1, +3, +5 and +7 post-BMT. Treatment with 15d-PGJ2 resulted in a significantly reduced GVHD mortality (p=0.01 log rank test) with a Median Survival Time (MST) of 23 days in the control group. Median survival was not reached in the 15d-PGJ2 treatment group at the end of the observation period (day +50 post BMT). Furthermore, we found a significant reduction in donor T cell expansion of 15d-PGJ2-treated animals on day +6 post-BMT. To further delineate the mechanisms underlying its protective effect, we analyzed the effects of 15d-PGJ2 on alloantigen-driven proliferation in MLR cultures in vitro as well as development and maturation of mouse bone marrow derived- dendritic cells (DC) in vitro. Treatment with 15d-PGJ2 resulted in a dose-dependent inhibition of allo-antigen driven proliferation. Furthermore, using a 12-day culture system 15d-PGJ2 led to a significant reduction of mature DC as determined by the number of DC co-expressing CD40, CD80, CD86. Treatment for 24 hours with 5uM of 15d-PGJ2 significantly inhibited activation of the NF-κB pathway as demonstrated by abrogation of p65 and IkB-α phosphorylation in response to alloactivation and also in 15d-PGJ2 treated DC using western blot analysis. In conclusion our data support the notion that the inhibitory effect of 15d-PGJ2 on the development of GVHD involves NF-κB-dependent inhibition of DC maturation and expansion of donor T cells. Given its potent antitumor effects cyclopentenone prostaglandins could be ideal candidates for prevention of GVHD while maintaining Graft versus malignancy effects.