T细胞疫苗接种对实验性自身免疫性脑脊髓炎大鼠免疫机制的调节作用

目的　探讨 T细胞疫苗 ( TCV)接种对实验性自身免疫性脑脊髓炎 ( EAE)免疫机制的调节作用。方法　取正常及 EAE大鼠腹股沟淋巴结细胞 ,经 MBP抗原诱导 ,制备 MBP特异的 TCV用于接种 ,以 HE染色观察髓鞘病变 ,MTT法检测细胞毒反应 ,FACS方法检测 T细胞亚群 ,ELISA方法检测血清中细胞因子含量。结果　接种 TCV后 ,CD8 细胞百分率上升 ,T细胞对脑细胞的杀伤率下降 ,血清中 IFN-γ与 TNF-α含量下降以及脑髓质炎症反应减弱 ,EAE发病率下降。结论　特异性 TCV接种可降低自身免疫反应性。 TCV通过淋巴细胞亚群的变化及细胞因子的调节 ,发挥对 EAE的免疫预防和治疗效应     

髓鞘少突胶质细胞诱导实验性自身免疫性脑脊髓炎小鼠的中枢病理损伤与Th1、Th17细胞分泌炎症细胞因子的变化观察

目的：观察实验性自身免疫性脑脊髓炎（EAE）的中枢神经系统（CNS）病理损伤与Th1、Th17细胞分泌的相关炎症细胞因子的变化,探讨EAE致病的分子免疫学机制。方法：用髓鞘少突胶质细胞（MOG35-55）免疫诱导野生型C57BL／6小鼠制作EAE模型,记录小鼠行为学变化,苏木精-伊红染色观察CNS病理损害,RT-PCR法检测中枢Th1细胞因子γ-干扰素（IFN-γ）、Th17细胞因子IL、17和IL-6的mRNA表达水平。结果：MOG诱导的EAE模型组小鼠出现典型的EAE行为及病理学表现,大脑组织中INF-γ、IL-17和IL-6mRNA表达水平均较CFA对照组有明显升高。结论：在EAE炎症反应的过程中,Th1细胞和Th17细胞激活,各自分泌的炎症细胞因子（INF-γ／IL-6、IL-17）增加,它们可能参与了EAE发病的重要免疫病理机制。EAE的致病并不是单-Th1或者Th17细胞作用的结果,而是两类细胞因子都参与了作用。     

多发性硬化的免疫治疗研究

多发性硬化（multiplesclerosis，MS）及其动物模型实验性自身免疫性脑脊髓炎（experi－mentalautoimmuneencephalomyelitis，EAE）可能是神经系统的自身免疫性疾病，以神经系统的炎症、脱髓鞘和星形细胞增生为特征。近年来，对于其发病机制的研究进展较快，认为MS是一种主要由T细胞介导的免疫性疾病，一些炎症性细胞因子（cytokine，Ck）如IFNr、LT、TNFa、IL－1等在其发病中起重要作用，通过一些抑制剂来恢复这些炎性细胞因子的平衡似乎是一种可能治疗的途径。目前研究较多的主要包括两大类即Ck抑制剂和抑制性Ck。1Ck抑制剂Ck抑…     

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。     

小胶质细胞活化在实验性自身免疫性脑脊髓炎中的作用机制

目的探讨小胶质细胞活化在实验性自身免疫性脑脊髓炎(EAE)发病机制中的作用。方法利用同种脑脊髓匀浆诱导EAE模型。采用免疫组化法、免疫组织荧光染色观察小胶质细胞对EAE不同病期炎性脱髓鞘病灶的反应,采用免疫组化法、ELISA法观察脑组织及外周血肿瘤坏死因子α(TNF-α)的表达。结果EAE发病前小胶质细胞即开始激活并持续至高峰期,形态学上表现为从正常的细小分枝状逐渐演变为高度分枝状、阿米巴状。免疫组化染色显示TNF-α阳性细胞多为小胶质细胞。EAE大鼠发病前脑组织中小胶质细胞、TNF-α阳性细胞数及外周血TNF-α水平已升高并持续至高峰期。结论小胶质细胞活化伴随EAE发病的整个过程。活化后的小胶质细胞可能通过合成和释放多种炎症介导物及细胞因子如TNF-α,进一步扩大炎症反应,进而促使髓鞘病变。     

B细胞免疫调控在重症肌无力中的作用

B细胞是重症肌无力(MG)发病的直接参与者,其免疫调控对疾病发生发展起重要作用。B细胞是一种抗原提呈细胞,与其他的免疫细胞互相作用产生自身抗体,除此之外,还具有其他一些特殊功能,如通过分泌细胞因子调控树突状细胞(DC)及T细胞功能,激活T细胞的免疫调控等。调节性B细胞通过分泌调节性细胞因子,细胞间接触等发挥免疫抑制功能。鉴于B细胞及其他免疫细胞在MG发病中的作用,新的针对B细胞的治疗策略已引起广泛关注。     

细胞因子与多发性硬化的关系

细胞因子是由多种细胞,特别是免疫细胞所产生的小分子蛋白质(分子量约8～80kDa),在免疫调节、免疫细胞的分化发育、炎症反应等众多环节中发挥了重要的作用.而多发性硬化(MS)是一种主要由T细胞介导的自身免疫性疾病,其中CD4+的Th1型T细胞的过度增殖可能是MS发病的重要因素[1].实验进一步证明:通过测定脑脊液和血液中相关细胞因子的含量可了解机体免疫功能的状况;通过补充或拮抗细胞因子可产生调节免疫的生物学效应.本文就细胞因子的生物学活性和效应机制等方面与多发性硬化(MS)的发病、转归和治疗的内在联系综述如下.     

多发性硬化患者血清及脑脊液中白细胞介素-10、-12的水平

多发性硬化（MS）是一种自身免疫性疾病，细胞因子（cytokine，CK）在MS及其动物模型实验性变态反应性脑脊髓炎（EAE）的免疫致病中起重要作用。我们于2000-2005年间用酶联免疫吸附（ELISA）技术检测我院诊治的复发-缓解型MS患者血清及脑脊液中白细胞介素-10（IL-10）、IL-12的水平，旨在从细胞分子免疫角度进一步探讨MS的免疫学发病机制，为MS的诊疗提供依据。     

阿托伐他汀对实验性自身免疫性脑脊髓炎脑组织IL-1β、IL-6影响的研究

目的探讨实验性自身免疫性脑脊髓炎（EAE）豚鼠脑组织细胞因子的变化,探讨阿托伐他汀对EAE发病保护作用的免疫调节机制。方法粗制碱性髓鞘蛋白抗原（Wistar大鼠全脊髓匀浆）＋完全福氏完全佐剂（CFA）免疫豚鼠建立EAE模型。40只豚鼠分成正常对照组、EAE对照组、EAE低剂量组和EAE高剂量组,每组10只,雌雄各半;放射免疫法测定正常对照组、EAE各组高峰期脑组织IL-1β、IL-6含量。结果EAE对照组、EAE低剂量组和EAE高剂量组脑组织IL-1β、IL-6水平显著高于正常对照组,EAE高、低剂量组脑组织IL-1β、IL-6水平比EAE对照组低,EAE高剂量组脑组织IL-1β、IL-6水平比EAE低剂量组低（P〈0.05）。结论EAE豚鼠存在明显免疫功能紊乱,阿托伐他汀有降低EAE模型脑组织IL-1β、IL-6水平作用,其对EAE发病的免疫保护机制可能是通过抑制IL-1β、IL-6产生而发挥。     

转化生长因子-β与实验性变态反应性脑脊髓炎

多发性硬化 (multiple sclerosis,MS)是人类的一种自身免疫性疾病 ,而实验性变态反应性脑脊髓炎 (experience autoim-mune encephalomyelitis,EAE)则是研究 MS的经典动物模型。在 EAE的发病机制和治疗方面 ,有关细胞因子的深入探讨方兴未艾 ,其中转化生长因子 - β(Transformin     

Recent advances in the immunopathology of experimental autoimmune encephalomyelitis: With special reference to cytokine production in the central nervous system

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that can be induced by immunization with encephalitogenic antigens such as myelin basic protein. Recent in vitro studies have demonstrated that cytokines play an important role in immune reactions in the central nervous system (CNS), suggesting that cytokines released by infiltrating cells and glial cells may contribute to the pathogenesis of EAE. In this review, we focus on the interactions between infiltrating cells and brain cells during the inflammatory process in EAE and discuss the roles of cytokines in the CNS. After immunization with proper myelin antigens, encephalitogenic T cells increase in number and infiltrate the CNS parenchyma via the subarachnoid space or the blood vessels. Once inflammatory cells infiltrate the CNS, microglia and astrocytes are activated, and some of these cells proliferate in response to cytokines released by infiltrating cells. Following this, activated microglia present antigens to induce T cell proliferation and cytokine production. In contrast, astrocytes induce T cell unresponsiveness, probably due to a lack of costimulatory signals. Furthermore, infiltrating T cells are the main producers of Th1 cytokines and are involved in T cell-brain cell interactions. This cascade of events indicates that immune reactions take place in the CNS, although the CNS has previously been considered to be an immunologically privileged site. Based on these findings, we also discuss the feasibility of using various cytokines to stimulate the immunomodulation of brain inflammation as a treatment for autoimmune demyelinating diseases.     

Serum pro-inflammatory and anti-inflammatory cytokines and the pathogenesis of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) as an experimental model of multiple sclerosis (MS) is characterized by demyelination, infiltration of inflammatory cells into the nervous system and dysregulation of serum inflammatory cytokines. We investigated the correlation of serum cytokines and other inflammatory markers with the EAE pathogenesis. After EAE induction, the levels of different serum cytokine/inflammatory mediators were measured. Furthermore, motor functions, myelination, and lymphocyte infiltration in EAE mice were also assessed. Our results revealed that the serum concentrations of T-helper 1 (Th1) and Th17 cytokines, interleukin (IL)-6, IL-1β, IL-1α and prostaglandin E2 in EAE mice were significantly higher than controls. The ratios of pro- to anti-inflammatory cytokines were different between the EAE and the control group. A statistically significant positive correlation was found between the IL-6/IL-10 ratio and the EAE severity, demyelination rate, and lymphocyte infiltration in EAE mice. Results indicate that the profiles of serum pro- and anti-inflammatory cytokines might be useful as biomarkers for monitoring the pathological manifestation of EAE. Furthermore, evaluating the dynamic interplay of serum cytokine levels and the correlation with pathogenic mechanisms of EAE may provide diagnostic and therapeutic insights for MS and some other inflammatory disorders.     

Epicutaneously induced TGF-beta-dependent tolerance inhibits experimental autoimmune encephalomyelitis

Experimental allergic encephalomyelitis (EAE) is an animal model of multiple sclerosis. While EAE is mediated by the cytokines produced by specific T cells, the cytokine signature of these effector cells is unresolved. We tested CD4 cells from MOG peptide 35-55 immunized C57BL/6 mice for their peptide induced cytokine production on antigen presenting cells of the respective cytokine knockout mice, or wild type mice. IL-4 and IL-6 production was seen on wild type antigen presenting cells, suggesting that IL-4 and IL-6 are not T cell products. In contrast, IFN-gamma, IL-2 and IL-3 were found to be produced by the MOG specific CD4 cells. Understanding the cognate vs. bystander cytokine production in EAE might help dissect the contribution of cytokines to the pathogenesis of the disease.     

Characterization of acute versus chronic relapsing autoimmune encephalomyelitis in DA rats

This study was undertaken to better understand the role of cytokines in the pathogenesis, especially in the mechanisms of relapse, of experimental autoimmune encephalomyelitis (EAE). For this purpose, we induced acute and chronic relapsing (CR) EAE in DA rats and determined several immunological parameters in rats at various stages of two types of EAE. Histopathological analysis revealed that there was no significant difference in the severity of inflammation in the spinal cord lesions between the two groups. However, demyelination was observed only in rats with CR EAE. Cytokine analysis by competitive PCR demonstrated that levels of TNF-alpha, IL-6 and IL-12 p40 mRNA in the spinal cord at the first attack of CR EAE were significantly higher than those at the peak stage of acute EAE. The mRNA expression of anti-inflammatory cytokines, IL-10 and TGF-beta1, was generally low in both acute EAE and the first attack of CR EAE and upregulated at later stages of CR EAE. These findings suggest that persistent high-level expression of pro-inflammatory cytokines is closely associated with demyelination and relapse of EAE. In contrast, anti-inflammatory cytokines play only a minor role in the relapse.     

The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review

The female predominance of multiple sclerosis (MS) has suggested that hormonal differences between the sexes must confer some protective effect on males or enhance the susceptibility of females to this disease. There has been evidence that gonadal hormones can modulate the immune response regulated by antigen presenting cells and T cells. These cells control the immune response by the production of interacting pro- and anti-inflammatory cytokines. The first include the acute phase pro-inflammatory cytokines of the innate immune response as well as the T-helper 1 (Th1) cytokines, while the later contain the Th2 cytokines as well as the suppressor cytokines. There is some evidence that MS and experimental autoimmune encephalitis (EAE) are Th1 cell-mediated diseases. For this reason many studies have been done to influence the pro-inflammatory cytokine production of these Th1 cells in favour of an anti-inflammatory immune response as mediated by Th2 cells. However the role of the regulatory T cells in this context is not clearly understood. Here we review the studies concerning the role of sex hormones on the cytokine production in relation to the disease course of MS and EAE and in particular in the light of the recent revival of the regulatory T cells and their suppressive cytokines.     

Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis

The ability of sex hormones to regulate cytokine production is well established, but the ability of cytokines to regulate sex hormone production has only begun to be investigated. We measured sex hormones in mice with passive experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS) patients with sexual dysfunction. Abnormally low serum testosterone levels were found in male mice with EAE and in male MS patients, while serum estrogen levels in female mice with EAE were normal. An inverse relationship between cytokine and testosterone levels in male mice with EAE, coupled with an increase in serum luteinizing hormone (LH) levels, suggests that inflammatory cytokines suppress testosterone production by a direct effect on testicular Leydig cells. Gender differences in the sensitivity of the hypothalamic–pituitary–gonadal (HPG) axis to inflammation may be an important factor regulating the duration and severity of central nervous system (CNS) autoimmunity.     

Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a mouse model for multiple sclerosis, where disease is mediated by autoantigen-specific T cells. Although there is evidence linking CD4⁺ T cells that secrete IL-17, termed Th17 cells, and IFN-γ-secreting Th1 cells with the pathogenesis of EAE, the precise contribution of these T cell subtypes or their associated cytokines is still unclear. We have investigated the infiltration of CD4⁺ T cells that secrete IFN-γ, IL-17 or both cytokines into CNS during development of EAE and have examined the role of T cells in microglial activation. Our findings demonstrate that Th17 cells and CD4⁺ T cells that produce both IFN-γ and IL-17, which we have called Th1/Th17 cells, infiltrate the brain prior to the development of clinical symptoms of EAE and that this coincides with activation of CD11b⁺ microglia and local production of IL-1β, TNF-α and IL-6 in the CNS. In contrast, significant infiltration of Th1 cells was only detected after the development of clinical disease. Co-culture experiments, using mixed glia and MOG-specific T cells, revealed that T cells that secreted IFN-γ and IL-17 were potent activators of pro-inflammatory cytokines but T cells that secrete IFN-γ, but not IL-17, were less effective. In contrast both Th1 and Th1/Th17 cells enhanced MHC-class II and co-stimulatory molecule expression on microglia. Our findings suggest that T cells which secrete IL-17 or IL-17 and IFN-γ infiltrate the CNS prior to the onset of clinical symptoms of EAE, where they may mediate CNS inflammation, in part, through microglial activation.     

B7-2(CD86)协调刺激因子在急性实验性变态反应性脑脊髓炎(AEAE)发挥主导作用

目的　探讨协调刺激分子B7 1(CD80 )和B7 2 (CD86)在急性EAE发病过程中的作用。方法　观察抗B7 1和B7 2抗体在体外对淋巴细胞抗原特异性增殖反应和细胞因子分泌的抑制作用和在体内对EAE发生过程的影响。结果　抗B7 2抗体抑制PLP136 150抗原引起的特异性细胞增殖和IL 2产生 ,抗B7 2抗体处理过的淋巴母细胞诱导轻症被动EAE ;在主动EAE诱导的早期抗B7 2抗体虽能延缓发病时间但加重病情 ,可能与IL 4分泌不足有关 ;当临床EAE首发症状出现时 ,抗B7 2抗体减轻其临床表现。结论　协调刺激分子B7 2在AEAE发生过程中发挥重要作用