PDF(Pubmed)
Abstract：
BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival.
METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection.
RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats.
CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection.
RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats.
CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
摘要：
背景：临床试验提供了证据，表明多巴胺能前体的移植，可以被新的体外干细胞来源所取代，可以整合到宿主组织中，缓解帕金森病（PD）的运动症状。在一些患者中，在观察到移植物衍生的功能改善后几个月发生了移植物功能的恶化。外周器官的排斥反应最初与HLA特异性抗体有关。然而,现在认为非HLA抗体的作用也与排斥反应相关.血管紧张素II型1受体自身抗体（AT1-AA）充当AT1受体的激动剂。AT1-AA是与移植不同实体器官和造血干细胞后的移植物功能障碍或排斥反应最广泛相关的非HLA抗体。然而,尚不清楚AT1-AA在多巴胺能移植物中的存在和可能的功能作用，以及使用AT1受体阻滞剂（ARB）如坎地沙坦治疗对移植物存活的影响。
方法：在6-羟基多巴胺PD大鼠模型中，我们研究了短期（10天）和长期（3个月）的影响与ARB坎地沙坦慢性治疗移植多巴胺能神经元和小胶质细胞移植物浸润的存活，以及多巴胺能神经支配和移植对血清和CSFAT1-AA水平的影响。通过激光捕获显微切割确定移植神经元中AT1受体的表达。
结果：在嫁接后的早期，移植的多巴胺能神经元存活的数量在治疗和未治疗的宿主之间没有显着差异(即，对照大鼠和用坎地沙坦治疗的大鼠)，可能是因为,就在嫁接之后,其他有害因素是多巴胺能细胞死亡的主要因素，比如机械性创伤,缺乏生长因子/营养和缺血。然而,移植后几个月，在坎地沙坦治疗组中,我们观察到存活的多巴胺能神经元数量显著增加,纹状体多巴胺能终末密度较高.几个月来,移植大鼠的血液和脑脊液AT1-AA水平高于正常对照组，AT1-AA水平也高于非嫁接帕金森病大鼠。
结论：结果表明，在PD患者中使用ARB如坎地沙坦，特别是在多巴胺能移植之前和之后，以及需要监测PD患者的AT1-AA水平，特别是在多巴胺能移植的候选人中。
方法：在6-羟基多巴胺PD大鼠模型中，我们研究了短期（10天）和长期（3个月）的影响与ARB坎地沙坦慢性治疗移植多巴胺能神经元和小胶质细胞移植物浸润的存活，以及多巴胺能神经支配和移植对血清和CSFAT1-AA水平的影响。通过激光捕获显微切割确定移植神经元中AT1受体的表达。
结果：在嫁接后的早期，移植的多巴胺能神经元存活的数量在治疗和未治疗的宿主之间没有显着差异(即，对照大鼠和用坎地沙坦治疗的大鼠)，可能是因为,就在嫁接之后,其他有害因素是多巴胺能细胞死亡的主要因素，比如机械性创伤,缺乏生长因子/营养和缺血。然而,移植后几个月，在坎地沙坦治疗组中,我们观察到存活的多巴胺能神经元数量显著增加,纹状体多巴胺能终末密度较高.几个月来,移植大鼠的血液和脑脊液AT1-AA水平高于正常对照组，AT1-AA水平也高于非嫁接帕金森病大鼠。
结论：结果表明，在PD患者中使用ARB如坎地沙坦，特别是在多巴胺能移植之前和之后，以及需要监测PD患者的AT1-AA水平，特别是在多巴胺能移植的候选人中。
