Jablonska Anna, Janowski Mirosław, Lukomska Barbara
NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.
Acta Neurobiol Exp (Wars). 2013;73(1):88-101. doi: 10.55782/ane-2013-1924.
Cerebrovascular diseases are the leading cause of severe disability worldwide, with an enormous financial burden for society. There is growing evidence that stem cell-based therapy may positively influence recovery from stroke. Cord blood is an attractive source of ontogenetically young, yet safe, stem cells. Conceptually, preclinical studies in which donor cells were of human origin have been the most valuable, and thus, it is likely that these cells will be used in clinical trials. Unfortunately, immunological barriers impede discordant xenotransplantations. We have previously observed acute rejection of cord blood derived neural stem cells (HUCB-NSC) after transplantation to the brains of intact animals. Since it was reported recently that a brain lesion may actually improve the chances of graft survival, in this study, we used infarcted animals as graft recipients. In ongoing studies, we tested three immunosuppressive regimes: group I received cyclosporine A (CsA: 10 mg per kg i.p.); group II received a triple-drug therapy (CsA: 10 mg per kg i.p., azathioprine: 5 mg per kg i.p., and methylprednisolone: 1.5 mg per kg i.m.); group III included rats that were formerly desensitized with HUCB, group IV had not undergone immunosuppression. Animals were sacrificed at five time-points: 1, 3, 7, 14, and 21 days post-transplantation to evaluate graft survival and the time-course of immunological response. We observed a gradual decrease in the number of transplanted cells, with complete disappearance by day 14, surprisingly, with no difference among the experimental groups. The involvement of the innate immune system in the process of graft rejection dominated over an adaptive immunoresponse, with the highest activity on day 3, and subsequent fading of immune cell infiltration. In this work, we have shown that none of our immunosuppressive strategies proved adequate to prevent rejection of human stem cell grafts after transplantation into immunocompetent animals.
脑血管疾病是全球严重残疾的主要原因，给社会带来了巨大的经济负担。越来越多的证据表明，基于干细胞的疗法可能对中风恢复产生积极影响。脐带血是一种具有吸引力的、源自发育早期且安全的干细胞来源。从概念上讲，供体细胞为人类来源的临床前研究最具价值，因此这些细胞很可能会用于临床试验。不幸的是，免疫屏障阻碍了非协调性异种移植。我们之前观察到，将脐带血来源的神经干细胞（HUCB-NSC）移植到完整动物的大脑后会出现急性排斥反应。由于最近有报道称脑损伤实际上可能会提高移植存活的几率，在本研究中，我们将梗死动物用作移植受体。在正在进行的研究中，我们测试了三种免疫抑制方案：第一组接受环孢素A（CsA：腹腔注射10毫克/千克）；第二组接受三联药物疗法（CsA：腹腔注射10毫克/千克，硫唑嘌呤：腹腔注射5毫克/千克，甲泼尼龙：肌肉注射1.5毫克/千克）；第三组包括先用HUCB进行脱敏的大鼠，第四组未进行免疫抑制。在移植后的1、3、7、14和21天这五个时间点对动物实施安乐死，以评估移植存活情况和免疫反应的时间进程。我们观察到移植细胞数量逐渐减少，到第14天完全消失，令人惊讶的是，各实验组之间没有差异。先天性免疫系统在移植排斥过程中的参与程度超过了适应性免疫反应，在第3天活性最高，随后免疫细胞浸润逐渐消退。在这项研究中，我们表明，在将人类干细胞移植到具有免疫能力的动物体内后，我们的任何一种免疫抑制策略都不足以防止移植排斥。
