Al-Homsi Ahmad Samer, Goodyke Austin, Cole Kelli, Muilenburg Marlee, McLane Michael, Abdel-Mageed Sarah, Feng Yuxin
Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI; Michigan State University College of Human Medicine, Grand Rapids, MI.
Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
Exp Hematol. 2017 Apr;48:50-57. doi: 10.1016/j.exphem.2016.12.002. Epub 2016 Dec 19.
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 naïve 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.
对于异基因造血干细胞移植（HSCT）后预防移植物抗宿主病（GvHD）的创新方法一直有着持续的需求。自从蛋白酶体抑制剂引入临床实践以来，通过抑制树突状细胞（DC）来预防GvHD的研究兴趣再度兴起。伊沙佐米是一种口服生物利用度高的蛋白酶体抑制剂，蛋白酶体解离速率快。我们研究了伊沙佐米对人DC体外成熟、活力和细胞因子产生的影响。我们还确定了伊沙佐米在小鼠GvHD模型中的作用。尽管伊沙佐米抑制了未成熟人DC的成熟，但对细胞活力的影响有限。伊沙佐米降低了静息DC的促炎细胞因子产生。当DC预先受到刺激时，这种作用减弱或逆转。在体内，与GvHD组相比，移植后第+1天和+4天或-1天、+2天和+5天给予伊沙佐米可改善GvHD。尽管按照延长方案治疗的一部分小鼠在第+5天治疗后突然死亡，但两种方案均导致总体生存率提高。当我们研究伊沙佐米对脾细胞和血清细胞因子的影响时，发现伊沙佐米发挥了复杂的、依赖给药方案的免疫调节作用。我们的研究为伊沙佐米在预防GvHD中的潜在应用提供了理论依据。
