Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion

作者：Al-Homsi, Ahmad Samer^*; Goodyke, Austin; Cole, Kelli; Muilenburg, Marlee; McLane, Michael; Abdel-Mageed, Sarah; Feng, Yuxin

来源：Experimental Hematology, 2017, 48: 50-57.

DOI：10.1016/j.exphem.2016.12.002

• NF-KAPPA-B
• MARROW-TRANSPLANTATION
• METHOTREXATE
• BORTEZOMIB
• GVHD
• CYCLOSPORINE
• PROPHYLAXIS
• ACTIVATION
• LEUKEMIA

There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. We also determined the effects of ixazomib in a murine GvHD model. Although ixazomib suppressed naive human DC maturation, it had only a limited effect on cell viability. Ixazomib decreased pro inflammatory cytokine production of resting DCs. This effect was diminished or reversed when DCs were pre-stimulated. In vivo, ixazomib administered post-transplantation on days +1 and +4 or days 1, +2, and +5 ameliorated GvHD in comparison to the GvHD group. Although a fraction of mice treated according to the prolonged schedule died abruptly after the day +5 treatment, both schedules resulted in improved overall survival. When we examined the effects of ixazomib on splenic cells and serum cytokines, we found that ixazomib exerted complex schedule-dependent immunomodulatory effects. Our study provides a rationale for the potential use of ixazomib in the prevention of GvHD.

• 出版日期2017-4
• 单位天津中医药大学