Borlongan C V, Stahl C E, Cameron D F, Saporta S, Freeman T B, Cahill D W, Sanberg P R
Department of Surgery, University of South Florida College of Medicine, Tampa 33612, USA.
Neurol Res. 1996 Aug;18(4):297-304. doi: 10.1080/01616412.1996.11740425.
Neural transplantation therapy as a possible alternative treatment for neurological movement disorders, such as in Parkinson's disease (PD), has accentuated research interest on the immune status of the central nervous system (CNS). Most animal studies concerned with neural transplantation for the treatment of PD have utilized dopamine (DA) neurons from tissues of the embryonic ventral mesencephalon. Rat embryonic DA neurons, grafted either as solid blocks or dissociated into a cell suspension and stereotaxically injected intraparenchymally into a rat lesion model of PD, have been shown to survive and form connections with the host brain, and ameliorate the behavioral deficits of PD. Similarly, studies on nonhuman primate models of PD provide considerable support for neural transplantation of DA neurons as an experimental clinical procedure for the treatment of PD. To this end, experimental clinical trials have been centered upon transplantation of the embryonic ventral mesencephalic cells for PD patients. Although not conclusive, the findings from clinical studies have provided some evidence that most patients with marked increases in fluorodopa uptake (indicating graft survival) have been immunosuppressed. Furthermore, immune reactions have been observed in rats xenografted with human embryonic tissue. Of note, embryonic ventral mesencephalic tissues compared to adult tissues produce better morphological and long-lasting behavioral amelioration of the neurobehavioral deficits of PD, thus advocating the use of grafts from young donors (embryo) to circumvent the CNS immune rejection. The possible graft rejection due to CNS immune reactions, coupled with the social and ethical problems surrounding the use of embryonic neural tissue, and the logistical problems concerning tissue availability have prompted the development of alternative sources of DA-secreting cells. To circumvent these obstacles, several methods have been suggested including the use of immunosuppressants such as Cyclosporine-A, transplantation of autografts, polymer-encapsulated DA-secreting cells, co-culturing and co-transplantation of DA-secreting cells with microcarrier beads, with Sertoli cells, or with fragments of a monoclonal antibody that can mask the MHC class I antigens, and genetically modifying cells that can withstand CNS immune reactions. Some of these techniques allow transplantation of allograft (same species transplantation), or even xenograft (cross species transplantation) without immunosuppression of the recipient. We discuss recent CNS immunosuppression techniques that pose some promise for enhanced survival of neural grafts. When possible, advantages and disadvantages of each method are presented. Hopefully, such critical analysis of different immunosuppression techniques will produce innovated ideas that will lead to a better understanding of CNS immune response and its modulatory function on graft rejection and survival.
神经移植疗法作为治疗神经运动障碍（如帕金森病（PD））的一种可能的替代疗法，已引发了对中枢神经系统（CNS）免疫状态的研究兴趣。大多数关于神经移植治疗PD的动物研究都使用了来自胚胎腹侧中脑组织的多巴胺（DA）神经元。已证明，作为实体块移植或解离成细胞悬液并立体定向脑内注射到PD大鼠损伤模型中的大鼠胚胎DA神经元能够存活并与宿主脑形成连接，改善PD的行为缺陷。同样，对PD非人灵长类动物模型的研究为DA神经元的神经移植作为治疗PD的实验性临床程序提供了相当多的支持。为此，实验性临床试验一直以向PD患者移植胚胎腹侧中脑细胞为中心。虽然尚无定论，但临床研究结果已提供了一些证据，表明大多数氟多巴摄取显著增加（表明移植物存活）的患者都接受了免疫抑制。此外，在异种移植了人类胚胎组织的大鼠中观察到了免疫反应。值得注意的是，与成体组织相比，胚胎腹侧中脑组织在改善PD神经行为缺陷方面产生了更好的形态学和持久的行为改善，因此主张使用来自年轻供体（胚胎）的移植物来规避CNS免疫排斥。由于CNS免疫反应可能导致的移植物排斥，加上围绕使用胚胎神经组织的社会和伦理问题，以及有关组织可用性的后勤问题，促使人们开发分泌DA细胞的替代来源。为了克服这些障碍，人们提出了几种方法，包括使用免疫抑制剂如环孢素A、自体移植、聚合物包裹的分泌DA细胞、将分泌DA细胞与微载体珠、支持细胞或能掩盖MHC I类抗原的单克隆抗体片段共培养和共移植，以及对能够耐受CNS免疫反应的细胞进行基因改造。其中一些技术允许在不抑制受体免疫的情况下进行同种异体移植（同物种移植），甚至异种移植（跨物种移植）。我们讨论了最近的CNS免疫抑制技术，这些技术对提高神经移植物的存活率有一定的前景。如有可能，还介绍了每种方法的优缺点。希望对不同免疫抑制技术的这种批判性分析能产生创新想法，从而更好地理解CNS免疫反应及其对移植物排斥和存活的调节功能。
