2-Methoxyestradiol Treatment Prevents Graft-versus-Host Disease While Preserving Graft-versus-Leukemia Effect in Mice

Abstract

2-Methoxyestradiol (2ME2, Panzem) is an endogenous metabolite that is well-tolerated in phase I/II clinical trials for variety of tumors. The plasma levels of 2ME2 may increase up to 1,000-fold during pregnancy and correlate temporally with the remission of rheumatoid arthritis (RA) and multiple sclerosis (MS) symptoms. The anti-inflammatory properties of 2ME2 were recently established in the mouse model of MS, and the mechanism of action is the ability of 2ME2 to inhibit lymphocyte proliferation, cytokine production and T cell polarization. Herein, we have demonstrated that 2ME2 treatment can significantly reduce the mortality and morbidity associated with graft-versus-host disease (GVHD). There is a lower number of donor-derived CD4+ and CD8+ T cells in the peripheral lymph node and Peyers patches of 2ME2-treated mice compared to control recipients. Moreover, 2ME2 exposure can significantly decrease the production of IFN-{gamma} and IL-2 in donor-derived CD4+ T cells and serum in GVHD mice. However, 2ME2 treatment has no effect on the differentiation of CD8+ effector T cells in vivo and their cytolytic activity remains intact. Furthermore, 2ME2 therapy is effective in preventing GVHD while preserving graft-versus leukemia (GVL) activity in mice. Our findings indicate that 2ME2 could be a novel and effective treatment for GVHD patients.