Teriflunomide reduces behavioral,electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis

Teriflunomide is an orally available anti-inflammatory drug that prevents T and B cell proliferation and function by inhibition of dihydroorotate dehydrogenase. It is currently being developed for the treatment of multiple sclerosis (MS). We report here for the first time the anti-inflammatory effects of teriflunomide in the Dark Agouti rat model of experimental autoimmune encephalomyelitis (EAE). Neurological evaluation demonstrated that prophylactic dosing of teriflunomide at 3 and 10 mg/kg delayed disease onset and reduced maximal and cumulative scores. Therapeutic administration of teriflunomide at doses of 3 or 10 mg/kg at disease onset significantly reduced maximal and cumulative disease scores as compared to vehicle treated rats. Dosing teriflunomide at disease remission, at 3 and 10 mg/kg, reduced the cumulative scores for the remaining course of the disease. Teriflunomide at 10 mg/kg significantly reduced inflammation, demyelination, and axonal loss when dosed prophylactically or therapeutically. In electrophysiological somatosensory evoked potential studies, therapeutic administration of teriflunomide, at the onset of disease, prevented both a decrease in waveform amplitude and an increase in the latency to waveform initiation in EAE animals compared to vehicle. Therapeutic dosing with teriflunomide at disease remission prevented a decrease in evoked potential amplitude, prevented an increase in latency, and enhanced recovery time within the CNS.     

Optic neuritis in children with poor recovery of vision

We reviewed the records of 10 children with optic neuritis in whom recovery of vision was poor or incomplete. Our cases were otherwise similar to those described in previous studies in that they were always bilateral, often accompanied by a viral prodrome (seven of 10), and usually associated with disc oedema (seven of 10).
Seven of twenty eyes had a final visual acuity of 6/60 or worse and only one patient regained 6/6 vision in either eye. In three patients the best vision in either eye was 6/60 or worse. Recovery of vision was often slow, taking up to six years. Five of 10 patients have developed multiple sclerosis (MS), and one child had acute disseminated encephalomyelitis (ADEM) with optic neuritis.
Optic neuritis in children does not always carry a good prognosis for recovery of vision; however, the failure of vision recovery in a short period of time does not necessarily indicate a poor outcome. Some children with optic neuritis develop MS, which can develop even when optic neuritis follows a viral illness.     

mRNA for NGF and p75 in the central nervous system of rats affected by experimental allergic encephalomyelitis

R. De Simone, A. Micera, P. Tirassa and L. Aloe (1996) Neuropathology and Applied Neurobiology 22, 54-59 mRNA for NGF and p75 in the central nervous system of rats affected by experimental allergic encephalomyelitis
In this study we measured the concentration of nerve growth factor (NGF) and the expression of NGF and the low affinity NGF-receptor (NGF-r) mRNA in the central nervous system (CNS) of rats affected by experimental allergic encephalomyelitis (EAE) during the acute phase of the disease. Significant levels of NGF protein were found in thalamus and cortex on day 13 postimmunization. Molecular analysis of the NGF gene expression and of its NGF-r revealed that they were enhanced in several regions of the CNS of EAE rats when compared with untreated animals. These results suggest a functional link between local NGF synthesis and this autoimmune inflammatory disease.     

Opposing effects of CTLA4-Ig and Anti-CD80 (B7-1) plus Anti-CD86 (B7-2) on experimental allergic encephalomyelitis

The roles of the B7 receptors, CD80 and CD86, during actively induced experimental allergic encephalomyelitis were examined with specific monoclonal antibodies and CTLA4-Ig. Injection of CTLA4-Ig on day 2 post-immunization resulted in decreased incidence and severity of resultant disease. Anti-CD80 injection on day 2 blocked development of the first disease episode. Subsequent relapses were unaffected. In contrast, injection of anti-CD86 alone had no effect. Surprisingly, combined anti-CD80 + anti-CD86 monoclonal antibody injection on day 2 resulted in marked exacerbation of disease. Examination of cytokine production in the draining lymph node cells demonstrated a reduction in both interferon (IFN)-γ and interleukin (IL)-2 producing cells, but a dramatic increase in tumor necrosis factor (TNF)-α secretion in animals receiving both monoclonal antibodies. These results suggest distinct roles for CD80 and CD86 in the initiation of EAE, resulting in the diverse clinical outcomes observed in this model of EAE.     

Acute disseminated encephalomyelitis following dengue fever

 A 58-year-old man suffered from acute disseminated encephalomyelitis (ADEM) after dengue fever. ADEM has not been described as the cause of neurological complications in dengue fever. However, the increasing use of magnetic resonance imaging in endemic areas may help to identify ADEM as being responsible for neurological complications in dengue fever. Received: November 9, 2001 / Accepted: December 14, 2001     

实验性自身免疫性脑脊髓炎大鼠血-脑脊液屏障功能及动态变化

目的　探讨实验性自身免疫性脑脊髓炎 ( EAE)大鼠血 -脑脊液屏障功能的动态变化及其作用 ,以求进一步揭示 EAE发病机制。方法　检测 EAE大鼠免疫后第 4、6、8、1 0、1 2、1 4、1 6、1 8、2 0天血清和脑脊液 ( CSF)中清蛋白 ( ALB)含量 ,其 CSF与血清 ALB比值 ( QA)作为评价血 -脑脊液屏障损害的指标。结果　 QA值免疫后第 8天即出现显著性升高 ,早于临床症状出现 ;随免疫时间的延长 QA值呈逐渐增高后缓慢下降趋势 ,并且 QA值与EAE大鼠病情评分呈显著正相关 ( r =0 .81 ,P =0 .0 0 1 )。结论　血 -脑脊液屏障的早期损害在 EAE发病过程中具关键作用。     

Changes in hypothalamic corticotrophin-releasing factor and anterior pituitary pro-opiomelanocortin mRNA during the course of experimental allergic encephalomyelitis

The pituitary-adrenal axis is activated during the course of experimental allergic encephalomyelitis (EAE), a paralytic disease resulting from an immunological reaction against central nervous system myelin. The magnitude of the adrenal response not only correlates with the severity of disease, but also serves an important functional role in recovery. We have shown that in EAE there are short-term changes in anterior pituitary pro-opiomelanocortin (POMC) mRNA as well as plasma corticosterone which can be detected before the development of clinical disease. At peak clinical signs when corticosterone and POMC mRNA are maximal, hypothalamic corticotrophin-releasing factor (CRF) mRNA is suppressed, suggesting that pituitary-adrenal activation is not mediated by CRF. Following recovery all parameters return to normal.     

Hepatitis A post-viral encephalitis

We report a seven-year-old girl who developed a hepatitis A viral infection and encephalitis. The patient developed fever, abdominal pains and jaundice. Five days later she became delirious, combative, and did not respond to verbal commands. Laboratory studies showed elevated liver enzymes and elevated serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis A virus. Cerebrospinal fluid contained IgG antibodies to hepatitis A virus but not IgM antibodies. Polymerase chain reaction, which amplifies a portion of the hepatitis A virus genome, did not demonstrate viral nucleic acid in cerebrospinal fluid. These studies suggest that the patient may have suffered from a post-viral hepatitis A encephalitis from which she fully recovered.     

Inflammatory mediators in demyelinating disorders of the CNS and PNS

Work in both experimental models and human disorders of the central and peripheral nervous system has delineated multiple effector mechanisms that operate to produce inflammatory demyelination. The role of various soluble inflammatory mediators generated and released by both blood-borne and resident cells in this process will be reviewed. Cytokines such as interleukin (IL)-1, interferon (IFN)-γ, and tumor necrosis factor (TNF)- are pivotal in orchestrating immune and inflammatory cell-cell interactions and represent potentially noxious molecules to the myelin sheath, Schwann cells, and/or oligodendrocytes. Arachidonic acid metabolites, synthesized by and liberated from astrocytes, microglial cells and macrophages, are intimately involved in the inflammatory process by enhancing vascular permeability, providing chemotactic signals and modulating inflammatory cell activities. Reactive oxygen species can damage myelin by lipid peroxidation and may be cytotoxic to myelin-producing cells. They are released from macrophages and microglial cells in response to inflammatory cytokines. Activation of complement yields a number of inflammatory mediators and results in the assembly of the membrane attack complex that inserts into the meylin sheath-creating pores. Activated complement may contribute both to functional disturbance of neural impulse propagation, and to full-blown demyelination. Proteases, abundantly present at inflammatory foci, can degrade myelin. Vasoactive amines may play an important role in breaching of the blood-brain/blood-nerve barrier. The importance of nitric oxide metabolites in inflammatory demyelination merits investigation. A better understanding of the multiple effector mechanisms operating in inflammatory demyelination may help to devise more efficacious antigen non-specific therapy.     

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