鼻黏膜诱导免疫耐受预防实验性自身免疫性脑脊髓炎机制的研究

目的：探讨鼻黏膜免疫耐受对实验性自身免疫性脑脊髓炎（EAE）的预防机制以及与耐受原相关的剂量依赖性。方法：建立Lewis大鼠EAE模型，用不同种属和剂量髓鞘碱性蛋白（MBP）诱导免疫耐受，评估EAE临床发病情况；检测特异性淋巴细胞增殖反应ELISPOT检测特异性单个核细胞IFN-γ表达及原位杂交方法检测相关细胞因子的变化。结果：经鼻黏膜给予低剂量（30μg／rat）和高剂量（600μg／rat）特异性抗原可诱导免疫耐受，抑制EAE的发生。淋巴细胞增殖实验显示，高、低剂量耐受组与对照组相比均可抑制特异性淋巴细胞增殖反应（P〈0．001；P〈0．01）。ELISPOT结果表明，与对照组相比高、低剂量耐受组单个核细胞IFN-γ表达数量明显降低（P〈0．01；P〈0．001）。原位杂交结果显示，与对照组相比，低剂量组IL-4mRNA的表达水平明显增高（P〈0．001），高剂量组未见明显增高（P〉0．05）。结论：经鼻黏膜可诱导机体产生免疫耐受，预防EAE的发生。给予低剂量抗原可引起Th1／Th2分泌的细胞因子发生偏离，产生免疫耐受。     

Peptide T does not ameliorate experimental autoimmune encephalomyelitis (EAE) in Lewis rats

Peptide T has been shown to inhibit T cell activation and cytokine production and function. Moreover, it has been reported to be a safe treatment in humans. We have studied the ability of peptide T to prevent or ameliorate EAE in Lewis rats. Peptide T was administered subcutaneously at different doses and phases of the disease according to several treatment protocols, but we could not observe a consistent effect of peptide T ameliorating the disease. Lymph node cell proliferation and IL-4 and interferon-gamma production were also studied. We conclude that peptide T neither prevents nor ameliorates EAE in Lewis rats.     

Increased expression of caveolin-1 and -2 in the hearts of Lewis rats with experimental autoimmune myocarditis

The expression of caveolin-1, -2 and -3 was studied in the hearts of rats with experimental autoimmune myocarditis (EAM), to elucidate the involvement of caveolins in the pathogenesis of EAM. Western blot analysis showed that levels of caveolin-1 and -2 were significantly increased in the hearts of rats with EAM on day 14 post-immunization (pi), as compared to the hearts of normal controls (p < 0.05, normal controls vs. EAM). Caveolin-3 is already at a high level in control animals, so it does not increase further.

Immunohistochemistry showed that caveolin-1 was expressed mainly in ED1-positive macrophages and in some cardiomyocytes and vessels in the EAM lesions. Caveolin-2 was expressed constitutively in the vascular endothelial cells of normal hearts, and its expression was enhanced in EAM rats, as compared with the normal control group. Caveolin-3 was expressed constitutively in the plasma membranes of cardiomyocytes, but not in the vascular endothelial cells and inflammatory cells in the EAM lesions. Our results suggest that the expression of caveolin-1 and -2 is increased in EAM lesions and that the increased expression of caveolin-1 stimulates second signals in affected cells, such as macrophages and some cardiomyocytes, in EAM rats.     

Transplantation of olfactory ensheathing cells promotes partial recovery in rats with experimental autoimmune encephalomyelitis

Objective: This study was to investigate the efficacy of olfactory ensheathing cell (OEC) transplantation on experimental autoimmune encephalomyelitis (EAE). Methods: EAE models were established by guinea pig spinal cord homogenate (GPSCH) immunization in Lewis rats. OECs were purified and cultured from the olfactory nerve layer of SD rats, and then transplanted to the EAE models through the vena caudalis (Group A) or into the lateral cerebral ventricle (Group B). Neurological function scores and body weights were daily recorded following transplantation, and histological analysis was performed to assess the pathological changes in EAE rats. Results: Cultured cells mainly exhibited bipolar or tripolar morphology, and the majority of these cells were positive for NGFR p75 staining. Neurological function scoring and the body weight measurement showed that, OEC transplantation could significantly improve the performance of EAE rats, and similar results were observed for the transplantation through the vena caudalis and into the lateral cerebral ventricle. Moreover, the transplanted OECs accumulated to the lesions in the brains of EAE rats, in spite of the different transplantation approaches. However, no significant differences in histopathology (HE and LFB staining) were observed between the OEC-transplanted groups and the control group. Conclusion: OEC transplantation could exert beneficial effects in the treatment of EAE, no matter which the cells were transplanted through the vena caudalis or into the lateral cerebral ventricle. Our findings might provide evidence for the clinical treatment of multiple sclerosis with cell transplantation.     

Dehydroepiandrosterone therapy ameliorates experimental autoimmune myasthenia gravis in Lewis rats

To detect a possible effect of dehydroepiandrosterone (DHEA) in the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), DHEA (0.5 mg/rat) was administrated intraperitoneally to Lewis rats every other day from day 4 postimmunization (p.i.) to day 35 p.i. with Torpedo acetylcholine receptor (AChR) and Freund's complete adjuvant. Rats treated with DHEA had a lower clinical score (mean clinic score, 2 versus 0.5 on day 37 p.i.) and a lower body weight loss (mean body weight, 169 versus 142 g on day 37 p.i.) compared with control EAMG rats. DHEA treatment decreased serum anti-AChR IgG and IgG2b antibody titers on days 7, 14, and 21 p.i. and inhibited the levels of anti-AChR IgG antibody secreting cells (60%), accompanied by decreased IL-4 (33%) and augmented TGF-1-positive cells (41%) among lymph node mononuclear cells. These results obtained from EAMG in Lewis rats further encourage us to study DHEA treatment in human MG.     

Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse

Chronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice recapitulates many of the clinical and histopathological features of human multiple sclerosis (MS), making it a preferred model for the disease. In both, adaptive immunity and anti‐myelin T cells responses are thought to be important, while in MS a role for innate immunity and complement has emerged. Here we sought to test whether complement is activated in crEAE and important for disease. Disease was induced in Biozzi ABH mice that were terminated at different stages of the disease to assess complement activation and local complement expression in the central nervous system. Complement activation products were abundant in all spinal cord areas examined in acute disease during relapse and in the progressive phase, but were absent in early disease remission, despite significant residual clinical disease. Local expression of C1q and C3 was increased at all stages of disease, while C9 expression was increased only in acute disease; expression of the complement regulators CD55, complement receptor 1‐related gene/protein y (Crry) and CD59a was reduced at all stages of the disease compared to naive controls. These data show that complement is activated in the central nervous system in the model and suggest that it is a suitable candidate for exploring whether anti‐complement agents might be of benefit in MS.     

Identification of genomic regions controlling experimental autoimmune uveoretinitis in rats

The present study attempts to identify specific genetic locicontributing to experimental autoimmune uveoretinitis (EAU)susceptibility in F₂ progeny of resistant Fischer (F344/N) andsusceptible Lewis (LEW/N) inbred rats. F₂ progeny of F344/Nx LEW/N inbred rats were immunized with the R16 peptide of interphotoreceptorretinoid-binding protein (IRBP). A genome-wide scan was conductedusing 125 simple sequence length polymorphism markers in selectedF₂ animals that developed severe eye disease or remained unaffectedto identify phenotype:genotype co-segregation. The F₂ population(n = 1287) demonstrated a wide range of histologically assessedEAU scores (assessed on a scale of 0–4). The disease incidenceand severity were not consistent with a simple Mendelian inheritancemodel. Of the F₂ hybrid rats, 60% developed EAU, implying theexistence of a potent susceptibility locus with incomplete penetranceassociated with the LEW genome or a more complex polygenic modelof inheritance. Two genomic regions, on chromosomes 4 and 12,showed strong genetic linkage to the EAU phenotype (P < 0.0016),suggesting the presence of susceptibility loci in these chromosomalregions. In conclusion, we have identified two genomic candidateintervals from D4Arb8 to D4Mit17 on chromosome 4 and from thechromosome end to D12Arb8 on chromosome 12, that appear to influenceEAU susceptibility in LEW/F344 rats. Further analysis of thesegenomic regions may lead to identification of the susceptibilitygenes and to characterization of their function.     

Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat

Lymphocytes enter the central nervous system (CNS) in response to virus infections and in autoimmune diseases, such as multiple sclerosis (MS), but the origin of such lymphocytes is unclear. This study investigates the role of the cervical lymph nodes as a source of lymphocytes involved in experimental autoimmune disease of the brain. Acute active experimental autoimmune encephalomyelitis (EAE) is used as a model for the autoimmune aspects of MS and is characterized by lymphocyte and monocyte invasion and microglial activation, mainly in the spinal cord, 12–15 days post-inoculation (dpi) of antigen. Few lesions occur in the cerebral hemispheres in acute EAE, but a cryolesion to the surface of the brain 8 dpi results in a six-fold enhancement of cerebral EAE. The present study tests the hypothesis that cervical lymphadenectomy will reduce the enhancement of cerebral EAE induced by a cryolesion. Acute EAE was induced in 25 Lewis rats and a cryolesion to the brain, 8 dpi, in 16 rats was immediately followed by either cervical lymphadenectomy (n=8) or sham lymphadenectomy (n=8). The severity of EAE at 15 dpi, in the brain and spinal cord, was evaluated using immunocytochemistry for T lymphocytes (W3/13) and MHC class II expression (OX6). The results of the study showed that cervical lymphadenectomy reduced the level of cerebral EAE induced by a cryolesion by 40 per cent when compared with the sham-operated animals (P<0·01). This suggests that cervical lymph nodes play a pivotal role in the induction of EAE in the brain, possibly as a site for ‘priming’ T cells to target the brain. Investigation of the interrelationships between cervical lymph nodes and the brain in man may lead to new therapeutic strategies for multiple sclerosis. © 1997 John Wiley & Sons, Ltd.     

Galectin isolated from parasite inhibits remission of experimental autoimmune encephalomyelitis by up‐regulating autoantibody

Recently, parasite infections or parasite‐derived products have been suggested as a therapeutic strategy with suppression of immunopathology, which involves the induction of regulatory T cells or/and T helper type 2 (Th2) responses. In a recent study, researchers reported that constructed recombinant galectin (rTl‐gal) isolated from an adult worm of the gastrointestinal nematode parasite Toxascaris leonina attenuated clinical symptoms of inflammatory bowel disease in mice treated with dextran sulphate sodium. Noting the role of rTl‐gal in inflammatory disease, we attempted to investigate the effect of the parasite via its rTl‐gal on neuronal autoimmune disease using experimental autoimmune encephalomyelitis (EAE), a mouse inflammatory and demyelinating autoimmune disease model of human multiple sclerosis. In this model, rTl‐gal‐treated experimental autoimmune encephalomyelitis (EAE) mice failed to recover after the peak of the disease, leading to persistent central nervous system (CNS) damage, such as demyelination, gliosis and axonal damage. Further, rTl‐gal‐treated EAE mice markedly increased the number of CD45R/B220⁺ B cells in both infiltrated inflammation and the periphery, along with the increased production of autoantibody [anti‐myelin oligodendrocyte glycoprotein (MOG)_35–55] in serum at chronic stage. Upon antigen restimulation, rTl‐gal treatment affected the release of overall cytokines, especially interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α. Our results suggest that galectin isolated from a gastrointestinal parasite can deliver a harmful effect to EAE contrary to its beneficial effect on inflammatory bowel disease.     

Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat.

The influence of the immunosuppressive antibiotic agent 15-deoxyspergualin (DSG) on macrophages and autoreactive T helper lymphocytes from Lewis rats was analysed in vitro and in vivo. DSG did not inhibit antigen- or mitogen-induced proliferation of encephalitogenic or neuritogenic T helper cell lines in vitro. However, the presence of DSG during in vitro activation of the T cells strongly suppressed or completely abrogated their capacity to induce encephalitis (EAE) or neuritis (EAN) after adoptive transfer to naive rats, although expression of activation markers or adhesion molecules on the T line blasts was not down-regulated by DSG. Like activation-induced T cell proliferation, IL-2-dependent growth of CD4+ T line cells was not affected by DSG. Preincubation of CD4+ T line cells in DSG during IL-2-driven proliferation for 48 h, however, inhibited the subsequent antigen- but not mitogen-induced activation of these T cells, although neither density of T cell receptors nor other surface molecules involved in antigen recognition were lowered on the cells exposed to DSG. Similar to its effect in vitro, in vivo administration of DSG for 10 days even at a concentration with cumulative toxicity did not suppress in vitro proliferation of spleen cells induced by mitogen or a mitogenic combination of anti-CD2 antibodies. Furthermore, spleen cell and peripheral blood lymphocyte (PBL) surface antigens, particularly MHC molecules, were not altered by long-term treatment with DSG for 30 days. While there was a slight reduction in the number of polymorphonuclear cells in both populations, the proportion of the different leucocyte subpopulations remained unchanged. In contrast to the strong functional impact of DSG on autoreactive T helper cells, the drug did not inhibit the oxidative burst of macrophages or their MHC antigen expression. This study demonstrates a clear inhibitory effect of DSG on CD4+ T lymphocytes, but not macrophages. It provides an explanation for recent observations of a strong immunosuppressive in vivo effect of DSG on transplantation rejection and experimental autoimmune diseases, despite a normal mitogen response of T cells exposed to DSG in vivo and in vitro.     

Propofol hemisuccinate suppression of experimental autoimmune encephalomyelitis

Propofol hemisuccinate is a prodrug water soluble form of the lipophilic, phenolic compound propofol (2,6-di-isopropylphenol), that is the active ingredient in the widely used anesthetic agent Diprovan. Propofol binds to GABA_A receptors but also has a phenolic structure that confers antioxidant properties to the molecule. The effects of propofol hemisuccinate in rat experimental autoimmune encephalomyelitis (EAE) were studied using different doses and time regimes. Propofol hemisuccinate, 100 mg/kg given three times a day from day 7 or day 12 until day 16 after disease initiation, significantly reduced maximal EAE score. Histology studies supported the clinical findings demonstrating reduction in the inflammatory response in the lumbar spinal cord in animals treated with propofol hemisuccinate. Decreased levels of nitrotyrosine and unchanged levels of induced nitric oxide synthase suggest propofol hemisuccinate crossed the blood brain barrier and exerted its effects by lowering reactive oxygen species levels. The results suggest that propofol hemisuccinate may provide an alternative mode of treatment for acute exacerbations of multiple sclerosis.     

实验性变态反应性脑脊髓炎大鼠单核细胞趋化蛋白-1的表达与临床评分的相关性

目的：探讨实验性变态反应性脑脊髓炎（EAE）大鼠脑和脊髓中单核细胞趋化蛋白-1（MCP-1）的表达及其与临床评分的关系。方法：将Wistar大鼠分为正常组、佐剂（CFA）组和EAE组,取脑和脊髓制成石蜡切片,进行HE染色和MCP-1mRNA的原位杂交,并与各项临床指标比较。结果：EAE组的体重减轻、MCP-1 mRNA表达的阳性细胞百分数与正常大鼠、佐剂组相比显著性增加。EAE组大鼠MCP-1 mRNA的表达呈动态性变化,其MCP-1 mRNA先于临床症状高表达,并随临床评分的升高而升高,与临床评分呈正相关。结论：MCP-1是参与EAE发病的重要的炎性介质。     

Suppression of experimental autoimmune encephalomyelitis in Lewis rats by antibodies against CD2

The immunotherapeutic potential of three anti-rat CD2 monoclonal antibodies (mAb) (OX34, OX54, OX55) and the combination of OX54 with OX55 was tested in Lewis rat experimental autoimmune encephalomyelitis (EAE). In actively induced EAE, a single injection of OX34 2 days before immunization with myelin basic protein (MBP) in complete Freund's adjuvant (CFA) completely prevented or greatly attenuated EAE in all animals. Injection of OX54 acted moderately suppressive while OX55 or OX54/55 did not affect disease severity. Abrogation of EAE by OX34 was not restricted to its application before immunization. Therapeutic administration of all three mAb and the Ab combination from onset of first clinical signs efficiently blocked progression of disease and prevented all animals from developing hind limb paresis. In adoptive transfer EAE induced with in vitro activated cells of an encephalitogenic T helper line, clinical and histological signs were completely prevented by injection of OX34 on the day of cell transfer and 4 days later, underlining the strong impact of anti-CD2 mAb on the effector phase of disease. Immunocytofluorometric analysis of peripheral blood lymphocytes after a single Ab injection demonstrated that all mAb induced a variable degree of transient reduction in T cell numbers and modulation of CD2 antigens. In contrast to the other mAb, OX34 persisted on lymphocytes for at least 11 days, which may explain its unique suppressive effect on EAE after a single injection before immunization. The assumption that prophylactic administration of OX34 also inhibits MBP-induced EAE, due to persistence into the effector phase, was substantiated by the finding that none of the mAb prevented generation of an antigen-specific cellular response in MBP/CFA-immunized animals. Since none of the Ab induced T cell unresponsiveness or inhibited T cell activation by antigen- or Ab-mediated stimulation of the T cell receptor, we suggest that their marked action on the effector phase of EAE may rely on inhibition of T cell infiltration into the central nervous system. The demonstrated efficacy of these anti-CD2 mAb in EAE suggests a potential therapeutic role that may be equal to that of anti-CD4 or anti-T cell receptor Ab.     

三氧化二砷对大鼠自身免疫性葡萄膜炎疗效的初步观察

目的探讨三氧化二砷(ATO)对自身免疫性葡萄膜炎(EAU)大鼠模型的疗效及机制。方法用光感受器间维生素A类结合蛋白(IRBP)R14多肽免疫雌性Lewis大鼠后,随机分为ATO 5 mg/kg、2 mg/kg、0.5 mg/kg、环孢素A(CsA)2 mg/kg和对照组0.9%氯化钠注射液2mL/kg 5组,每组5只,分别每日腹腔注射。裂隙灯显微镜观察大鼠眼前房炎性反应,第15天时观察大鼠眼球的病理改变及质量变化,免疫组化观察大鼠眼球中T-bet+Th1及FOXP3+调节性T细胞浸润情况。结果 0.9%氯化钠注射液组和ATO 0.5 mg/(kg.d)组可见明显的前房炎性反应,ATO 5 mg/(kg.d)组和CsA组炎性反应较轻。CsA组、ATO 5 mg/(kg.d)组和ATO 2 mg/(kg.d)组的临床评分均显著低于0.9%氯化钠注射液组(P<0.05)。病理评分显示各组间有显著差异(P<0.05)。CsA组、ATO5 mg/(kg.d)组和ATO 2 mg/(kg.d)组病理评分均显著低于0.9%氯化钠注射液组(P<0.05)。与0.9%氯化钠注射液组比较,ATO 5 mg/(kg.d)组和CsA...     

The role of the ICOS/B7RP-1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis

ICOS/B7RP-1 is a new member of the CD28/B7 family of costimulatory molecules and plays differential roles in autoimmune diseases. In this study, we examined the role of ICOS/B7RP-1 pathway in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU), an animal model of human autoimmune uveitis. ICOS expression was found on infiltrating CD4+ T cells in the region of the retina in EAU-induced mice. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Moreover, administration of anti-B7RP-1 mAb effectively ameliorated the disease induced by adoptive transfer of pathogenic T cells. The anti-B7RP-1 mAb treatment inhibited the expansion and/or effector function of pathogenic T cells, given that proliferative response and IFN-gamma production by lymph node cells were reduced upon restimulation with the antigen peptide in vitro. These results suggest that the ICOS/B7RP-1 interaction plays a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Th1 disease induced in the same manner as EAU.     

Anatomical evidence for bulbospinal monoamine axon damage in rats with experimental allergic encephalomyelitis

Histofluorescence microscopy revealed extensive damage to bulbospinal catecholamine and indolamine axons in rats with paralysis induced by experimental allergic encephalomyelitis. The damaged axons were almost invariably located near perivascular inflammatory foci. Increased fluorescence intensity observed in affected axons and in their nuclei of origin is consistent with a build-up of transmitter substance similar to that following axonal transection.These results caution against over-emphasizing demyelination as the pathogenetic basis of experimental allergic encephalomyelitis. Injury to central monoaminergic neurons may be an important determinant of the somatic and visceromotor manifestations of the disease.     

Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice

Experimental autoimmune encephalomyelitis (EAE) was induced in a mouse model (C57/BL6) to investigate the antioxidant status of animals at various clinical stages of the disease. For this purpose, blood, brain and spinal cord samples from EAE mice were collected and examined at different scores following post-immunization with myelin oligodendrocyte glycoprotein (MOG). The clinical sign of mobility of animals on different days was associated with gradual increase in lipid peroxidation products (malondialdehyde, i.e. MDA) in brain and spinal cord. Changes in lipid peroxidation during EAE progression was inversely related to superoxide dismutase (SOD) activity in erythrocyte preparation. However, suppression of catalase in erythrocytes, tissue glutathione (GSH) and plasma total antioxidant capacity (FRAP assay) were the early events in EAE, occurred during scores 1 and 2. Biochemical alterations were corroborated with histopathological observations showing demyelination and inflammatory foci in central nervous system (CNS) of animals suffering from partial hind limb paralysis (score 3). These data suggest that generation of MDA in CNS is a continuous process during EAE induction and suppression of antioxidant factors are early events of the disease, but crucial in increasing the vulnerability of CNS to demyelinating lesions.     

红景天苷对实验性自身免疫性脑脊髓炎小鼠的干预作用与机制

目的:观察不同浓度红景天苷(salidroside)对实验性自身免疫脑脊髓炎(experimental autoimmuneencephalomyelitis,EAE)小鼠模型的作用,并探讨初步的作用机制.方法:建立实验性自身免疫性脊髓炎小鼠模型,免疫当天起给予高中低剂量的红景天苷灌胃,1次/d,共给药35 d.给药完成后,进行神经功能评分,TUNEL染色检测脊髓髓鞘组织的细胞凋亡情况,ATP水平检测试剂盒检测脊髓组织ATP含量水平,免疫印迹法检测线粒体内细胞色素c氧化酶(mito cyto-c)、胞浆中细胞色素c氧化酶(cyto cyto-c)、活化的含半胱氨酸的天冬氨酸蛋白水解酶-3(cleaved cas-3)与活化的含半胱氨酸的天冬氨酸蛋白水解酶-9(cleaved cas-9)蛋白表达水平.结果:红景天苷降低EAE小鼠的神经功能评分,后延发病时间;随红景天苷浓度升高,脊髓髓鞘组织的细胞凋亡数逐渐降低,脊髓组织ATP水平显著升高;EAE小鼠脊髓组织细胞胞浆中的cyto-c蛋白表达显著升高,同时cleavedcas-3与cleaved cas-9蛋白表达显著升高,红景天苷干预后,胞浆中cyto-c蛋白表达显著下降,同时cleaved cas-3与cleaved cas-9蛋白表达下降.结论:红景天苷对缓解实验性自身免疫性脊髓炎症状具有良好的效果,可能通过抑制内源性线粒体通路而降低脊髓组织细胞的凋亡而发挥作用.     

Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis

Carboxypeptidase N (CPN) is a member of the carboxypeptidase family of enzymes that cleave carboxy-terminal lysine and arginine residues from a large number of biologically active peptides and proteins. These enzymes are best known for their roles in modulating the activity of kinins, complement anaphylatoxins and coagulation proteins. Although CPN makes important contributions to acute inflammatory events, little is known about its role in autoimmune disease. In this study we used CPN^−/− mice in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Unexpectedly, we observed several EAE disease phenotypes in CPN^−/− mice compared to wild type mice. The majority of CPN^−/− mice died within five to seven days after disease induction, before displaying clinical signs of disease. The remaining mice presented with either mild EAE or did not develop EAE. In addition, CPN^−/− mice injected with complete or incomplete Freund's adjuvant died within the same time frame and in similar numbers as those induced for EAE. Overall, the course of EAE in CPN^−/− mice was significantly delayed and attenuated compared to wild type mice. Spinal cord histopathology in CPN^−/− mice revealed meningeal, but not parenchymal leukocyte infiltration, and minimal demyelination. Our results indicate that CPN plays an important role in EAE development and progression and suggests that multiple CPN ligands contribute to the disease phenotypes we observed.     

Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune encephalitis

The enzyme Fatty Acid Amide Hydrolase (FAAH) is a key regulator of the endogenous levels of a family of biologically active lipid mediators, the fatty acid amides. These include anandamide, oleoyl ethanolamide and palmitoyl ethanolamide, and their effects are mediated by a variety of downstream targets including cannabinoid receptors and peroxisome proliferator-activated receptors (PPARs). Activation of both of these may have anti-inflammatory and neuroprotective effects. Levels of all three mediators are low in normal nervous tissue, but substantially elevated in mice lacking FAAH as a result of genetic deletion. There is a long anecdotal history of cannabis use by patients suffering from multiple sclerosis, and preclinical studies have indicated beneficial effects of cannabinoid receptor stimulation on both long-term outcome and acute muscle spasm in rodent models of multiple sclerosis (experimental autoimmune encephalitis; EAE). Thus far no report has appeared on the effect of inhibition of FAAH on the progression of EAE. Using a chronic mouse EAE model, we present data indicating that mice lacking FAAH experience an initial inflammatory phase of EAE similar in severity to wild type controls, but exhibited a more substantial clinical remission compared to wild type mice.