Reynolds Ashley D, Banerjee Rebecca, Liu Jianou, Gendelman Howard E, Mosley R Lee
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
J Leukoc Biol. 2007 Nov;82(5):1083-94. doi: 10.1189/jlb.0507296. Epub 2007 Aug 3.
Progressive loss of dopaminergic neurons in the substantia nigra pars compacta and their terminal connections in the striatum are central features in Parkinson's disease (PD). Emerging evidence supports the notion that microglia neuroinflammatory responses speed neurodegenerative events. We demonstrated previously that this can be slowed by adoptive transfer of T cells from Copolymer-1-immunized mice administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) recipients. The cellular basis for this neuroprotective response was the CD4+ T cell population, suggesting involvement of CD4+CD25+ regulatory T cells (Tregs), cells known to suppress immune activation and maintain immune homeostasis and tolerance. We show for the first time that adoptive transfer of CD3-activated Tregs to MPTP-intoxicated mice provides greater than 90% protection of the nigrostriatal system. The response was dose-dependent and paralleled modulation of microglial responses and up-regulation of glial cell-derived neurotrophic factor (CDNF) and TGF-beta. Interestingly, that adoptive transfer of effector T cells showed no significant neuroprotective activities. Tregs were found to mediate neuroprotection through suppression of microglial responses to stimuli, including aggregated, nitrated alpha-synuclein. Moreover, Treg-mediated suppression was also operative following removal of Tregs from culture prior to stimulation. This neuroprotection was achieved through modulation of microglial oxidative stress and inflammation. As Tregs can be modulated in vivo, these data strongly support the use of such immunomodulatory strategies to treat PD.
黑质致密部多巴胺能神经元及其在纹状体中的终末连接的进行性丧失是帕金森病（PD）的核心特征。新出现的证据支持小胶质细胞神经炎症反应加速神经退行性事件这一观点。我们之前证明，将来自共聚物-1免疫小鼠的T细胞过继转移给1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的受体，可以减缓这种情况。这种神经保护反应的细胞基础是CD4 + T细胞群体，提示CD4 + CD25 +调节性T细胞（Tregs）参与其中，已知这些细胞可抑制免疫激活并维持免疫稳态和耐受性。我们首次表明，将CD3激活的Tregs过继转移给MPTP中毒小鼠，可对黑质纹状体系统提供超过90%的保护。该反应呈剂量依赖性，与小胶质细胞反应的调节以及胶质细胞源性神经营养因子（CDNF）和转化生长因子-β（TGF-β）的上调平行。有趣的是，效应T细胞的过继转移未显示出明显的神经保护活性。发现Tregs通过抑制小胶质细胞对包括聚集的、硝化的α-突触核蛋白在内的刺激的反应来介导神经保护。此外，在刺激前从培养物中去除Tregs后，Treg介导的抑制作用仍然有效。这种神经保护是通过调节小胶质细胞的氧化应激和炎症实现的。由于Tregs可在体内进行调节，这些数据有力地支持了使用这种免疫调节策略来治疗PD。
