CSL Behring, King of Prussia, Prussia, PA, USA.
University of Toronto, Toronto, Ontario, Canada.
Am J Transplant. 2018 Jul;18(7):1589-1595. doi: 10.1111/ajt.14756. Epub 2018 Apr 24.
Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma-derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT-deficient individuals. Accumulating evidence suggests that AAT has additional anti-inflammatory and tissue-protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro- vs anti-inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune-modulatory effects of AAT and its well-established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.
供体器官的有限供应和缺血再灌注损伤（IRI）的风险严重限制了器官移植。能够预防或减少 IRI 的治疗方法可以通过增加边缘器官的使用和减少丢弃来潜在地增加移植数量。α-1 抗胰蛋白酶（AAT）是一种急性期反应物和丝氨酸蛋白酶抑制剂，可限制炎症性组织损伤。纯化的血浆衍生 AAT 在超过 30 年的使用中已被很好地耐受，用于预防 AAT 缺乏个体的肺气肿。越来越多的证据表明，AAT 具有额外的抗炎和组织保护作用，包括改善线粒体膜稳定性、抑制细胞凋亡、抑制核因子 kappa B 激活、调节促炎与抗炎细胞因子平衡以及促进免疫耐受。细胞培养和动物研究表明，AAT 可限制组织损伤并促进细胞和组织存活。AAT 通过下调早期炎症并有利于诱导和稳定调节性 T 细胞，在动物模型中可促进耐受。计划中和/或正在进行的临床试验应有助于确定动物和细胞研究的前景是否通过改善人类器官移植的结果得到实现。
