阿托伐他汀通过免疫调节作用治疗实验性自身免疫性脑脊髓炎

目的观察阿托伐他汀对实验性自身免疫性脑脊髓炎(EAE)小鼠的治疗作用,并研究相关机制。方法建立C57BL/6小鼠EAE模型,免疫成功后给予阿托伐他汀干预。应用Knoz评分观察小鼠的临床评分,免疫组化法观察IL-17浸润情况,流式细胞仪观察外周Treg细胞的分化情况,Western blot观察细胞外调节蛋白激酶/丝裂原活化蛋白激酶通路表达情况。结果阿托伐他汀可以改善EAE小鼠的神经功能缺损评分。免疫组化法显示阿托伐他汀可以减少IL-17在中枢神经系统的浸润,而流式细胞仪则发现阿托伐他汀可以促进外周Treg细胞的分化、降低外周脾细胞pERK的表达。结论阿托伐他汀可能通过ERK/MAPK通路调控TH17/Treg平衡进而改善EAE的神经功能缺损。     

细胞凋亡与实验性变态反应性脑脊髓炎

凋亡是细胞的一种主动死亡形式,与神经系统自身免疫性疾病的发生、发展和转归密切相关。本文对凋亡的形态、生化特征及其基因调控、T细胞的凋亡机制和糖皮质激素的影响以及凋亡在实验性变态反应性脑脊髓炎发病中的作用作一综述。     

阿托伐他汀对实验性变态反应性脑脊髓炎大鼠TNF-α和iNOS表达的影响

目的应用阿托伐他汀干预实验性变态反应性脑脊髓炎(experiment allergic encephalom yelitis,EAE)大鼠,探讨药物对于疾病发病、炎性细胞浸润及TNF-α和iNOS表达的影响。方法采用豚鼠脊髓匀浆诱导Wistar大鼠建立EAE模型,口服给药干预,观察药物对大鼠发病、炎性细胞浸润情况及TNF-α和iNOS表达的影响。结果阿托伐他汀降低了大鼠发病率(P<0.05),改善了大鼠发病的严重程度(P<0.05),抑制了炎性细胞向脊髓组织的的浸润(P<0.05),降低了脊髓中iNOS的表达(P<0.05),但对于血清中TNF-α的水平没有影响(P>0.05)。结论阿托伐他汀降低了大鼠的发病率,减轻了实验性变态反应性脊髓炎大鼠发病的严重程度及炎性细胞的浸润、iNOS的表达。     

实验性变态反应性脑脊髓炎与细胞凋亡

实验性变态反应性脑脊髓炎 (EAE)是研究人类多发性硬化 (MS)的经典动物模型 ,EAE发病和愈复过程中细胞凋亡的情况也是目前神经生物学的研究热点。研究者们发现 ,EAE时CNS损伤区有自身反应性T淋巴细胞的凋亡 ,而且这种细胞凋亡促进了EAE的愈复和耐受状态的形成 ,这就为EAE乃至人类MS的防治提供了一条新思路。有关EAE其他细胞凋亡和影响细胞凋亡的因素也有一些研究。本综述对近年来这些方面的研究进展做了较为全面的回顾     

调节性T细胞在实验性变态反应性脑脊髓炎和多发性硬化发病中的作用

调节性T细胞(regulatory T cells,Treg)是一类具有免疫调节功能的T细胞哑群.近年来,Treg细胞在实验性变态反应性脑脊髓炎(experimental allergical encephalomyelitis,EAE)、多发性硬化(multiple sclerosis,MS)发病中的作用越来越受到关注,小鼠Treg细胞缺失可导致特异性自身免疫性疾病,增加Treg细胞的功能可以减轻或抑制EAE.最近的研究结果表明,MS本身也伴随着成熟Treg细胞的受损或功能障碍.     

实验性变态反应性脑脊髓炎相关细胞因子

实验性变态反应性脑脊髓炎(EAE)是一种以细胞免疫为主,以中枢神经系统白质损害为特征的自身兔疫病。在其发病机理及病情演化中,由细胞因子构成的免疫网络起着重要的调节作用,其中一类是由单核巨噬细胞及Th1细胞分泌的致炎细胞因子能够促使EAE的发生或加重病情,而由Th2细胞分泌的免疫抑制性细胞因子又可抑制或逆转EAE的病情。本文收集近年来对EAE相关细胞因子的研究进行综述,以求反映人类多发性硬化疾病的免疫病理。同时还对近来在细胞因子的检测方法及细胞因子在EAE模型的预防和治疗中作用的研究新进展进行了介绍。     

阿托伐他汀对实验性自身免疫性脑脊髓炎的治疗作用

目的 观察不同剂量阿托伐他汀对实验性自身免疫性脑脊髓炎(EAE)的治疗效果,探讨其作用机制.方法 采用Wistar大鼠建立EAE模型,分别应用每日每千克体重2、8 mg的阿托伐他汀进行治疗,观察其对大鼠发病率、复发率、神经功能评分和组织病理改变的影响及程度,并测定基质金属蛋白酶-9(MMP-9)和IL-4在体内的表达及含量变化.结果 EAE模型组与大剂量治疗组相比较,神经功能评分有显著改善,发病率由76.67%下降至33.33%(P=O.008),脊髓组织中血管袖套数目由3.2±1.1减少为1.3±0.4(P=0.01),血清中IL-4的含量由(0.35±0.12)ng/ml显著提高至(0.68±0.23)ng/ml(P=0.05),MMP-9在组织中的表达由37±7减少至26±5(P=0.001).结论 阿托伐他汀能改善EAE的临床表现,减轻组织损伤,其作用可能与减少MMP-9和提高IL-4含量有关.     

甲基强的松龙治疗实验性变态反应性脑脊髓炎的作用机制

目的:研究细胞因子、T细胞凋亡和淋巴细胞增殖在实验性变态反应性脑脊髓炎(EAE)形成中的作用及甲基强的松龙(MP)治疗EAE的作用机制。方法:采用人脑纯化的髓鞘碱性蛋白(MBP)与完全福氏佐剂免疫Lewis大鼠,建立EAE动物模型。用双抗体夹心ELISA法检测各组大鼠血清中IL-10、TNF-α、IFN-γ的含量:流式细胞仪检测外周血T细胞凋亡;3H-TdR释放法检测外周血淋巴细胞转化率。结果:与对照组比较,EAE组的外周血IFN-γ、TNF-α水平明显增高,IL-10水平明显降低,MP治疗后IFN-γ和TNF-α水平下降,IL-10浓度上调。MP还诱导外周血T细胞凋亡和抑制MBP致敏淋巴细胞增殖并呈剂量依赖性。结论:应用人MBP成功建立EAE大鼠模型,MP可能通过调节Th细胞因子格局、促进Th2细胞因子分泌、抑制MBP致敏淋巴细胞增殖及外周血T细胞凋亡而发挥治疗多发性硬化的作用。     

实验性变态反应性脑脊髓炎的启动过程

实验性变态反应性脑脊髓炎（EAE）发病机制十分复杂，实验证据表明EAE是自身免疫性CD4^＋ T细胞即Th1细胞激活后介导的一系列级联免疫反应。在疾病过程中大量细胞因子作用于特异的免疫细胞，或细胞因子之间相互作用，形成复杂免疫网络，并贯穿疾病的始终。至于细胞因子是如何作用于特异的免疫细胞，从而启动这一中枢免疫级联反应的，是国内外研究一直关注的焦点。本文就近2年这一领域的研究进展进行了总结和分析，进一步揭EAE的发病机制。     

地塞米松对实验性变态反应性脑脊髓炎小鼠胸腺细胞凋亡的影响

目的 探讨地塞米松对实验性变态反应性脑脊髓炎（ＥＡＥ）小鼠胸腺细胞凋亡的影响。方法 采用昆明小鼠建立ＥＡＥ模型,于处死前２４小时腹腔注射米松,通过荧光染色法、原位末端标记法和电镜法观察地塞米松处理组,自然病程组和对照组的小鼠胸腺细胞凋亡。结果 地塞米松处理组的胸腺细胞凋亡率明显高于自然病程组和正常对照组（Ｐ〈０．０１）;且电镜发现有典型的凋亡改变。结论 地塞米松可明显增强ＥＡＥ小鼠胸腺细胞凋亡。     

Anti-endothelial cell antibody and immune complexes in the sera of animals with acute experimental allergic encephalomyelitis and chronic relapsing experimental allergic encephalomyelitis

Blood-brain barrier (BBB) injury occurs in both acute and chronic relapsing experimental allergic encephalomyelitis (EAE). Sera from animals in which these forms of EAE had been induced were examined for anti-endothelial cell antibodies and immune complexes by enzyme-linked immunosorbent assay (ELISA) using either cultured endothelial cells or Raji cells. IgG binding to endothelial cells was significantly increased in the sera of animals with acute EAE and chronic relapsing EAE, compared to controls. Increased levels of circulating immune complexes were also detected in the sera of some animals with chronic relapsing EAE, especially those in an exacerbation. It is suggested that the anti-endothelial cell antibody and immune complexes detected may play pathogenetic roles in the destruction of the BBB in EAE.     

实验性变态反应性脑脊髓炎大鼠穹窿下器的水肿观察

目的观察实验性变态反应性脑脊髓炎(EAE)大鼠不同时期穹窿下器(SFO)的水肿变化。方法建立大鼠EAE模型,分别用光镜和透射电镜观察EAE不同时期SFO的水肿改变。结果随病情进展,SFO的水肿逐渐加重,病情缓解后,水肿减轻。潜伏期至发病极期水肿主要局限在血管周围,恢复期水肿呈现弥散性。结论 SFO在EAE不同时期发生的水肿改变与临床进展呈一致性,参与了脑的免疫调节。     

Chronic relapsing experimental allergic encephalomyelitis

Summary The vascular permeability in the nervous system to Evans blue-albumin and horseradish peroxidase was studied in chronic relapsing EAE in strain 13 and Hartley guinea pigs. The disease was induced by single sensitization of immature animals and was characterized clinically by remissions and relapses. Recent and old demyelinating plaques in the spinal cord were present. These showed an increased permeability to the protein tracers. The blood-brain barrier in these plaques are therefore disturbed and also in this respect the condition is similar to the multiple sclerosis lesions.     

Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis

Mononuclear cell infiltration into the CNS and induction of inflammatory cytokines and iNOS in diseases like multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE) have been implicated in subsequent disease pathogenesis and progression. We report that Lovastatin treatment blocks the clinical disease and induction of inflammatory cytokines and iNOS in spinal cords of MBP induced EAE rats. A significant number of the infiltrating cells in CNS were ED1+ cells of monocyte/macrophage lineage. To understand the mechanism of efficacy of Lovastatin against EAE, we examined the effect of Lovastatin on the transmigration of mononuclear cells into EAE spinal cord. The data presented here documents that Lovastatin treatment attenuates the transmigration of mononuclear cells possibly by down regulating the expression of LFA-1, a ligand for ICAM, in endothelial-leukocyte interaction. These results indicate that Lovastatin treatment prevents infiltration by mononuclear cells into the CNS of rats induced for EAE, thereby lessening the histological changes and clinical signs and thus ameliorating the disease. These observations indicate that Lovastatin treatment may be of therapeutic value against inflammatory disease process associated with infiltration of activated mononuclear cells into the tissue.     

实验性变态反应性脑脊髓炎sIL-2R与TNF-α的检测

目的 研究可溶性白细胞介素-2-受体（sIL-2R)与肿瘤坏死因子-α（TNF-α）在实验性变态反应性脑脊髓炎（EAE）免疫学发病机制中的变化与作用。方法 应用豚鼠诱导EAE动物模型。在髓鞘碱性蛋白（MBP）与弗氏安全佐剂（CFA）免疫豚鼠的第8、15、22天处死动物，取脾细胞加入ConA诱生培养，收集上清液待测，采用酶联免疫吸附试验（ELISA）方法测定sIL-2R水平，采用生物活性测定法检测TNF-α水平。结果 EAE组的sIL-2R与TNF-α水平显著高于正常对照组。结论 sIL-2R与TNF-α在EAE免疫学发病机制中具有重要作用。本实验为深入研究多发性硬化（MS）的发病机制提供了理论依据。给MS免疫特异性治疗寻觅到新的线索。     

Similarities between the Forssman carotid syndrome and experimental allergic encephalomyelitis

Summary The Forssman carotid syndrome was induced in guinea pigs to study the mechanism of demyelination-like lesions in this animal model and to compare it with experimental allergic encephalomyelitis (EAE). Acute lesions were studied at 1–3 days after intracarotid injection of rabbit anti-Forssman antibody and chronic lesions at 7–21 days post injection, using routine histological, immunofluorescent, and electron-microscopic techniques. The results were compared to those in a group of guinea pigs with acute or chronic lesions of EAE. The picture was remarkably similar in the two conditions, in regard to localization in the central nervous system (CNS), composition of cellular infiltrates, diameter of lesions produced, myelin loss and axonal degeneration, together with gamma globulin deposition in small vessels in affected areas. The differences were that in the Forssman carotid syndrome, in contrast to EAE, there were no mononuclear cell infiltrates in the acute phase, and no evidence of macrophages invading myelin sheaths was detected. Perivascular lesions consisted of demyelination within infiltrates of mononuclear cell in chronic relapsing EAE, but not in the Forssman carotid syndrome. It is suggested that investigation of the distinction between the two models of the CNS may be of benefit in the pathogenetic study of demyelinating disease.Supported by the Epidemic Myalgic Encephalomyelitis Association and the Multiple Sclerosis Society of Great Britain     

T cell vaccination in monoclonal antibody-induced hyperacute experimental allergic encephalomyelitis

Demyelinating inflammatory disease of the central nervous system-(CNS) can be a multifactorial process mediated by cellular and antibody-mediated immune processes. In rats, hyperacute disease progression and severe demyelination can be induced in experimental allergic encephalomyelitis (EAE)-diseased animals by injection of a monoclonal antibody, 8-18C5, specific for an oligodendrocyte cell surface glycoprotein. Here we demonstrate that this antibody-induced hyperacute EAE can be prevented by 'vaccination' with myelin basic protein (MBP)-specific T cells. Thus, the 8-18C5 antibody-mediated disease process is critically dependent on inflammatory processes induced by T lymphocytes and T cell vaccination is highly effective in preventing the development of demyelinating CNS lesions.     

大鼠实验性变态反应性脑脊髓炎中一氧化氮的变化

目的　观察外周和中枢一氧化氮 (NO)在大鼠实验性变态反应性脑脊髓炎 (EAE)中的动态变化 ,探讨EAE大鼠发病的相关生物学机制。方法　 采用免疫组化法和硝酸还原酶法 ,观察豚鼠全脊髓匀浆诱导的Wistar大鼠EAE的过程中 ,脊髓内表达iNOS胶质细胞与外周NO代谢物NO 2 和NO 3的变化。 结果　 对照组脊髓内未发现表达iNOS阳性细胞 ,表达iNOS的CNS胶质细胞可能是小胶质细胞 ,而且它的变化与EAE大鼠的病情一致 ,评分 2分和 3分EAE大鼠脊髓表达iNOS的小胶质细胞比评分 1分大鼠明显增多 (P <0 .0 1) ,恢复期EAE大鼠表达iNOS的小胶质细胞明显减少 (P <0 .0 1)。EAE大鼠外周血清NO值随症状程度加重而升高 ,但在EAE恢复期时仍保持较高水平。未发病大鼠血清NO值明显增高 ,与对照组之间具有显著性差异 (P <0 .0 1)。 结论　 小胶质细胞产生的NO可能在急性期EAE大鼠的发病中起重要作用     

Antibodies-restricted heterogeneity in serum and cerebrospinal fluid of chronic relapsing experimental allergic encephalomyelitis

An animal model which might help to study multiple sclerosis has long been sought. With chronic relapsing experimental allergic encephalitis (EAE), the search seems to have brought hope and evidence of comparable pathology whether concerned with clinical or neuropathological results, but no study of the cerebrospinal fluid (CSF) electrophoretic pattern has been made so far. A new sensitive method enables to study the CSF proteins: unconcentrated CSF proteins after agar gel electrophoresis are stained with silver reagents. The silver technique allows to follow the evolution of the inflammatory reaction in chronic relapsing EAE as well as in the acute form of EAE. This technique provides an additional approach to the study of EAE and an argument in favor of chronic relapsing EAE in guinea pigs as a model for multiple sclerosis.