Porcine neural xenografts in the immunocompetent rat: Immune response following grafting of expanded neural precursor cells
Porcine neural xenografts in the immunocompetent rat: Immune response following grafting of expanded neural precursor cells
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DOI：
10.1016/s0306-4522(01)00273-1
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发表时间：
2001-01-01
期刊：
影响因子：
3.3
通讯作者：
Barker, RA
中科院分区：
文献类型：
--
作者：
Armstrong, RJE;Harrower, TP;Barker, RA
脑内异种神经移植引起宿主免疫反应，导致其快速排斥反应。这形成了异种组织移植治疗帕金森氏症等疾病的关键障碍。目前的研究试图深入了解供体细胞悬液中在刺激宿主排斥反应中起重要作用的细胞成分，从而建议合理处理异种供体组织，最终提高其临床应用价值。神经干细胞有丝分裂原，表皮生长因子和成纤维细胞生长因子-2，已被用于从胚胎猪脑中分离和扩增原始神经前体细胞群。在第一个实验中，将扩增的神经前体细胞移植到非免疫抑制的偏侧帕金森病大鼠体内，并在移植后10、21、35和60天检测移植物状态和宿主反应。当相同的初级组织移植物在35天完全消失时，具有健康神经丝阳性投射的扩大的神经前体移植物在所有时间点都存在，两个大的移植物即使在60天也保持不变。一些移植物在被检查的时间点上似乎引发了最小的宿主免疫反应，尽管大多数移植物似乎正在经历排斥过程，因为涉及宿主细胞毒性T淋巴细胞、小胶质细胞/巨噬细胞、免疫球蛋白M和补体的协同反应可以在不同程度上被证明。随后的实验进一步证明，扩大的前体群体和初级组织悬液在免疫原性方面有所不同。首先，当原始组织被注射到免疫活性大鼠的腹膜内时，会产生强烈的初级体液反应。在注射扩张的神经前体后，没有检测到这种反应。其次，流式细胞仪分析发现，猪主要组织相容性复合体在原代细胞悬液中有少量但显著的表达，而在扩大的前体细胞中没有表达。因此，本研究的结果表明，当神经干细胞有丝分裂原用于扩增前体细胞时，用于脑内移植的猪神经细胞悬液的免疫原性降低。这些发现的意义，在开发新的异种细胞疗法的神经退行性疾病，如帕金森氏病进行了讨论。(C)2001年IBRO。爱思唯尔科学有限公司出版。版权所有。
Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use of xenogeneic tissue transplantation for conditions such as Parkinson's disease. The current study sought to provide insight into the cellular components of donor cell suspensions that are important in stimulating the host rejection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neural stem cell mitogens, epidermal growth factor and fibroblast growth factor-2, have been used to isolate and expand populations of primordial neural precursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised.In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. While equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive projections were present at all time-points, and two large grafts remained even at 60 days. Some grafts appeared to elicit minimal host immune responses at the time-points they were examined, although most did appear to be undergoing a rejection process since a co-ordinated response involving host cytotoxic T-lymphocytes, microglia/wmacrophages, immunoglobulin M and complement could be demonstrated to varying degrees.Subsequent experiments went on to demonstrate further that expanded precursor populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursors. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations.The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral g-rafting is reduced when neural stem cell mitogens are used to expand precursor cells. The implications of these findings in the development of novel xenogeneic cellular therapies for neuro degenerative conditions such as Parkinson's disease are discussed. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.