The role of myelin lipids in experimental allergic encephalomyelitis: Part 2. Influence on disease production by encephalitogenic doses of myelin basic protein

Hartley guinea pig CNS myelin lipids (TL) were combined with an encephalitogenic dose (50 micrograms) of myelin basic protein (MBP) and injected together with complete Freund's adjuvant (CFA) into juvenile strain 13 guinea pigs. All the animals developed acute EAE and recovered, but only 50% had a single mild relapse during an observation period of 12 months. To determine the effect of individual myelin lipids on EAE, purified fractions comprising the galactocerebrosides (GC) or gangliosides (GANG) were combined with 50 micrograms MBP together with phosphatidyl choline (PC) and cholesterol (CHOL) and injected with CFA into juvenile Hartley guinea pigs. Control animals received MBP mixed with PC and CHOL or MBP alone, in CFA. The incidence of acute EAE was similar in all groups, but the highest percent recovery (69%) was seen in animals immunized with the MBP-GC combination. All animals that developed acute EAE in the control groups died. Histologically, CNS myelin breakdown was present during the acute attack except in the MBP control group. Parameters of cell-mediated immunity (CMI) showed good correlation with the clinicopathological findings in animals that received MBP-GC or MBP alone. In most animals, serum anti-MBP antibodies were detected as early as 10 days post-immunization (p.i.) whereas anti-lipid antibodies were found at 90 days p.i. Animals that received MBP-PC did not show any positive CMI or serum antibodies although they developed severe disease. The results indicate that myelin lipids, especially the galactocerebrosides, contribute to the development of chronic EAE; however, the mechanism by which this occurs is still obscure.     

Relapsing experimental allergic encephalomyelitis induced with isolated myelin and with myelin basic protein plus myelin lipids

To test the ability of different spinal cord fractions to reproduce the clinicopathological features of relapsing experimental allergic encephalomyelitis (R-EAE), groups of young guinea pigs were inoculated with: (1) spinal cord myelin; (2) delipidated myelin; (3) reconstituted myelin and (4) MBP plus myelin lipids. The four sets of antigens induced acute EAE in most of the animals tested. During an observation period of 18 months, only one clinical relapse was observed in animals sensitized with myelin and with MBP plus myelin lipids. Extensive CNS demyelination was found in relapsing animals injected with myelin. No demyelinated lesions were observed in non-relapsing animals. By contrast, half of the surviving guinea pigs injected with MBP plus myelin lipids had demyelinated lesions, irrespective of whether they relapsed or not. The inability of the spinal cord myelin fractions to fully reproduce the R-EAE model suggests that other non-myelin antigens may be involved in the pathogenesis of multiple relapses.     

Serum lipids and demyelination in experimental allergic encephalomyelitis induced by the increased encephalitogenicity of myelin basic protein given with galactocerebrospide

Cholesterol esters and free cholesterol were determined in the serum of guinea pigs with experimental allergic encephalomyelitis (EAE). EAE was induced by immunization with myelin basic protein (MBP) and galactocerebroside (GC). The results showed an increased content of cholesterol arachidonate and cholesterol linoleate during the period of clinical signs of EAE in comparison with the content of cholesterol esters in EAE induced by MBP without galactocerebroside. The content of free cholesterol was significantly reduced. Histological analyses showed intensive inflammatory lesions and demyelination which were not found in EAE induced by MBP without galactocerebroside.     

The role of myelin lipids in experimental allergic encephalomyelitis. Part 1. Influence on disease production by non-encephalitogenic doses of myelin basic protein

Hartley guinea pig central nervous system (CNS) myelin has been purified and fractionated into its protein and lipid components. Experimental allergic encephalomyelitis (EAE) was induced in juvenile strain 13 guinea pigs with both lyophilized and fresh 'wet' myelin. However, a larger dose of lyophilized myelin was required to induce chronic EAE. Total myelin lipids, galactocerebrosides, gangliosides, phospholipids or proteolipids were combined with a non-encephalitogenic dose of myelin basic protein (MBP) and injected in juvenile Hartley guinea pigs. No clinical or histological manifestations of disease were observed. Parameters of immune functions indicated that the total myelin lipids augmented cell-mediated immune responses as measured by in vitro lymphocyte transformation and by a significant decrease in the percentage of peripheral early T cells. Only the proteolipids elicited delayed hypersensitivity reactions. Animals that received the phospholipid-MBP combination showed no changes when compared to animals injected with MBP alone. The results suggest that although the myelin lipids did not act synergistically with a non-encephalitogenic dose of MBP to induce EAE, they induced immunological changes and potentiated the immune response to MBP.     

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. V. Hierarchy of suppression by myelin basic protein from different species.

We have been investigating the suppression of experimental autoimmune encephalomyelitis (EAE) by oral tolerization to autoantigens. In the present study the tolerizing effect of orally administered myelin basic protein (MBP) from different species was examined in the Lewis rat, Hartley guinea pig, and SJL/J mouse model of EAE. Animals were fed guinea pig, rat, bovine, human or mouse-MBP and then immunized with the homologous species of MBP or myelin: Lewis rats were immunized with rat MBP, Hartley guinea pigs with guinea pig-MBP, and SJL/J mice with mouse myelin. Clinical expression of EAE and delayed-type hypersensitivity (DTH) responses to MBP were assessed. In each species, suppression of disease and DTH responses were most pronounced by tolerization with the homologous species of MBP. In addition, cross-species tolerization was observed in each species and in general was less suppressive than homologous MBP although in some instances MBP from a heterologous species was as effective as tolerization with the homologous species. We also studied guinea pig-MBP induced EAE in the Lewis rat because it is a widely studied model of EAE and found that oral tolerization with guinea pig MBP was as suppressive as rat MBP. Of note is that oral tolerization with mouse MBP suppressed myelin-induced EAE in the SJL mouse in which autoimmunity to proteolipid protein appears to play a primary role, suggesting that antigen-driven bystander suppression following oral tolerization with autoantigens (Miller et al., 1991b) may be an important contributing mechanism for suppression of EAE following oral tolerization with MBP in this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of recurrent experimental allergic encephalomyelitis with myelin basic protein

Recurrent experimental allergic encephalomyelitis (EAE) was induced in Lewis rats by inoculation of human myelin basic protein (MBP) and complete Freund's adjuvant (CFA). The animals developed clinical disease characterized by unsteadiness, ataxic gait, and abnormal posturing of the limbs. Spontaneous remissions and relapses were noted for periods up to 120 days. Histologically there were perivascular infiltrates of mononuclear cells, especially prominent in the cerebellar white matter. There was little evidence of demyelination. This study demonstrates that relapsing EAE may be induced with MBP in the rat. Sensitization with other myelin antigens is not required, although immunity to such antigens may be necessary to induce demyelination. It is postulated that relapsing EAE may be associated with a defect in suppressor cell function.     

Suppression of acute and chronic experimental allergic encephalomyelitis in strain 13 guinea pigs: A clinical and pathological study

Adult inbred Strain 13 guinea pigs develop an acute, fatal form of experimental allergic encephalomyelitis (EAE) about 2 weeks after a single injection of isologous spinal cord in complete Freund's adjuvant (CFA), but similarly injected juveniles develop a delayed, rarely fatal chronic form. Thirty-seven sensitised adult Strain 13 animals were separated into 2 groups. One group was permitted to develop acute EAE. The other group was injected intramuscularly with 1 mg of guinea pig or bovine myelin basic protein (MBP) in incomplete Freund's adjuvant (IFA) on day 2, 7 or 10 post-inoculation (PI) followed by 0.2 mg in IFA every third day for a total of 10 doses. Animals in the unsuppressed group succumbed to acute EAE 13–16 days post-sensitisation. No animal in the suppressed group died during this period. Animals treated with MBP beginning 2 days PI showed no clinical signs, but mild clinical manifestations occurred in animals suppressed from days 7 and 10 PI. These signs remitted by 21 days post-sensitisation. One suppressed animal (out of 21) died during the fourth week postsensitisation. The other 20 suppressed animals appeared clinically normal towards the end of the course of MBP injections and remained so for the 6 months of study. Morphological examination revealed that CNS lesions occurred in all animals. In animals suppressed with MBP beginning on day 2 PI, lesions consisted only of a few meningeal inflammatory cells. Animals given MBP beginning on day 7 or 10 PI and sampled 1–2 weeks later, had lesions which could not be distinguished from those occurring in the non-suppressed acute EAE group. In time, the suppressed animals developed lesions which were typical of chronic EAE with remyelination as a predominant feature. Preliminary experiments on the suppression of chronic EAE in 5 juvenile Strain 13 guinea pigs have revealed that 3 MBP-injected animals failed to develop clinical disease over a 28-week period of study although lesions typical of chronic EAE were present. Simultaneously, 2 non-suppressed juvenile animals developed clinical signs by 12 weeks. These were associated with both acute inflammation and demyelination superimposed upon regions of chronic demyelinative activity.     

黄芩苷对实验性自身免疫性脑脊髓炎大鼠髓鞘的保护作用

目的观察黄芩苷(BAC)对实验性自身免疫性脑脊髓炎(EAE)大鼠髓鞘的保护作用。方法将大鼠随机分为正常对照(NC)组、EAE组、地塞米松(DXM)组和BAC组。抗原免疫1周后分别予以DXM组和BAC组大鼠DXM和BAC治疗7d;观察免疫后14d各组动物发病情况、脊髓病理变化及髓鞘碱性蛋白(MBP)的表达。结果(1)EAE组、DXM组和BAC组大鼠于抗原免疫后8～10d发病,发病潜伏期分别为9.62d、11.0d、9.85d,DXM组较EAE组潜伏期显著延长(P<0.05),BAC组与EAE组间差异无统计学意义;各组发病率分别为75.0%、66.7%、80%,各组间差异无统计学意义。(2)病程中EAE组和DXM组质量较BAC组明显下降(均P<0.05);DXM组和BAC组神经功能评分明显优于EAE组(均P<0.05)。(3)与EAE组比较,DXM组脊髓病灶数明显减少(P<0.05),BAC组病灶数有所减少,但差异无统计学意义。(4)与EAE组比较,DXM组和BAC组脊髓MBP阳性数显著增多(均P<0.05)。结论BAC对缓解EAE大鼠的临床症状、减轻髓鞘脱失的作用与DXM相似,而没有质量降低的不良反应。     

实验性自身免疫性脑脊髓炎的视神经病理改变

目的 研究实验性自身免疫性脑脊髓炎(EAE)的视神经病理改变.方法 足垫皮下注射豚鼠脊髓匀浆和完全弗氏佐剂(CFA)混合物制作Wismr大鼠EAE模型,于发病后第6d将大鼠处死,取视神经、脑和脊髓,行HE和LFB染色,光镜和电镜下观察其病理改变.结果 病理检查发现EAE模型组大鼠脑、脊髓有不同程度的炎症反应和脱髓鞘改变;均有视神经病变,光镜主要表现为炎症反应和脱髓鞘,视神经髓鞘脱失重于炎症反应;电镜主要表现为髓鞘稀疏,少突胶质细胞数量减少、胞核固缩,其周围包裹的髓鞘板层松解,轴突髓鞘分离.结论 EAE大鼠存在明显的视神经病变,主要为视神经炎症反应和脱髓鞘改变.     

特殊染色鉴定小剂量豚鼠脊髓匀浆诱导Wistar大鼠实验性自身免疫性脑脊髓炎模型的价值

目的特殊染色鉴定小剂量豚鼠脊髓匀浆诱导Wistar大鼠实验性自身免疫性脑脊髓炎模型的价值,并观察其病理的改变。方法按脊髓重量与冰盐水体积之比为1:5的比例制备豚鼠脊髓匀浆抗原,免疫Wistar大鼠,建立EAE模型;组织切片进行HE染色,三色染色,髓鞘碱性蛋白(MBP)及神经微丝(NF)免疫组化,光镜下观察病理改变。结果Wistar大鼠免疫后第16.07±4.25天发病,发病形式多样,除表现EAE经典症状外,尚出现痉挛状态、斜颈等特殊症状。HE染色发现神经组织内炎细胞浸润,血管"袖套"样病灶形成;三色染色可见轴突肿胀,呈串珠状,且不连续,着色不均匀;髓鞘结构层次紊乱,疏松,崩解;MBP及NF免疫组化研究发现病变组织内白质脱髓鞘及轴突损伤。结论三色染色结合MBP、NF免疫组化检测,较常规HE染色更能直接地、准确地显示EAE大鼠的病理变化,可推广应用。     

In vivo effect of sera from animals with chronic relapsing experimental allergic encephalomyelitis on central and peripheral myelin

Summary Sera from guinea pigs with acute or chronic relapsing experimental allergic encephalomyelitis (EAE) were injected into the lumbosacral subarachnoid space of normal recipient rats. Seventeen of 37 sera induced demyelination in the CNS, and 27 of 37 sera caused demyelinated peripheral nerve fibers in the roots. The highest incidence of demyelinating activity of EAE sera was noted in those from donor animals sampled during the early chronic stage of the disease [40–100 days post sensitization (dps)]. Only few sera from animals sampled during the acute and subacute stage (10–40 dps) were able to induce demyelination. Sera from animals sampled between 100 and 200 dps showed a lower incidence of demyelinating activity as compared to those from the early chronic phase of the disease. There was no clear-cut correlation between the serum-demyelinating activity and the severity of the demyelinating disease in the donor animals. The patterns of demyelination in the central as well as peripheral nervous system of recipient animals were characterized by vesicular disruption of myelin or myelin stripping. Myelin degradation was performed mainly by macrophages. In the CNS some astrocytes also contained debris. Astrocytes increased in size, and mitosis of astrocytes was observed. Oligodendrocytes appeared to be unaffected. No demyelination was found when the sera from animals sensitized with CFA alone or with guinea pig liver tissue were injeted into the subarachnoid space of normal recipient rats.Two possible mechanisms of demyelination are diseussed: Antibody-mediated complement-dependent and antibody-dependent cell-mediated demyelination.Supported in part by the Fonds zur Förderung der wissenschaftlichen Forschung, Austria, Project No. S-25/07     

Suppression of chronic-relapsing experimental allergic encephalomyelitis in strain-13 guinea pigs by administration of liposome-associated myelin basic protein

Juvenile strain-13 guinea pigs were challenged with isologous spinal cord in CFA. After recovery from the first EAE episode the animals were treated with guinea pig MBP inserted into liposomes, with cytochrome-c-liposomes, with MBP in saline or with MBP in IFA. Guinea pigs treated with MBP-liposomes showed a striking reduction in clinical signs and in the number and intensity of relapses. They displayed virtually no demyelinating lesions, and had comparatively little parenchymal inflammation in the spinal cord. Early T rosette levels showed an inverse correlation with the severity of histological lesions in the spinal cord but correlation with the clinical status at the time of rosette assay was less well defined.     

Studies on the encephalitogenic effects of purified preparations of human and bovine oligodendrocytes.

Bulk-isolated human and bovine oligodendroglia, practically free from myelin, have been used in attempts to elicit an autoimmune response which has been compared with acute experimental allergic encephalomyelitis (EAE). For these experiments, a total of 20 Hartley guinea pigs, 33 Lewis rats and 16 rabbits have been studied. Animals were inoculated with a range of doses of purified preparations of both human and bovine oligodendroglial cells in complete Freund's adjuvant (CFA) and compared with others challenged with whole white matter in CFA. The latter animals all developed clinical and histological signs of experimental allergic encephalomyelitis (EAE) 2-3 weeks post-inoculation. In general, oligodendroglial cells were encephalitogenically less potent than white matter. Guinea pigs were the most susceptible to inoculations of oligodendroglia. In several given human oligodendroglia 14 days earlier, a paraparesis indistinguishable from conventional EAE was seen. Animals receiving bovine cells showed no clinical signs. Histologically, the CNS of afflicted guinea pigs displayed severe inflammation but, in contrast to conventional EAE in the same species, demyelination was rare in the small group of animals tested. After sensitization with oligodendroglia, rats displayed no clinical disease. Histologically, some given human cells had positive evidence of disease while bovine cells in others gave a mild response. Rabbits showed no clinical and very little histological disease. Although more extensive studies are needed to confirm the findings, from the animals studied it appears that (1) variation in response to inocula containing oligodendroglia exists among the species tested, (2) that human oligodendroglia are more potent immunologically than bovine cells, (3) that CNS lesions produced by these cells in guinea pigs, lack a strong demyelinative component and (4) a specific antigen might exist in oligodendrocytes which is distinct from myelin basic protein. The possible reasons underlying our findings are discussed.     

Chronic neurologic dysfunction and demyelination induced in Lewis rats by repeated injections of encephalitogenic T-lymphocyte lines

Experimental autoimmune encephalomyelitis (EAE) in the Lewis rat is characteristically a monophasic paralytic disorder. Recovered rats are thereafter immune to EAE induced by injection of guinea pig basic protein (GP-BP) in complete Freund's adjuvant (CFA), but they are still susceptible to EAE induced by an encephalitogenic T-lymphocyte line (BP-1). Induction of active EAE or injection of a sublethal dose of activated BP-1 cells resulted in a monophasic episode of EAE, followed by recovery of normal neurologic function. Repeated challenges with activated BP-1 cells, however, induced unremitting neurologic signs marked by loss of tail tonicity and incontinence, which persisted for more than 6 months. Histologically, the spinal cord of affected rats revealed attenuation of MBP staining (demyelination) and moderate-to-extensive gliosis associated with increased size of intervening spaces. Inflammatory cell lesions, however, were notably absent. Biophysical analysis of isolated spinal cord myelin from affected rats demonstrated a distorted distribution in subfraction densities and the appearance of extra-myelin proteins in the light myelin subfraction. Immunologically, chronically affected animals were unresponsive to the encephalitogenic determinant on GP-BP, although other BP determinants elicited strong delayed type hypersensitivity (DTH) reactions in rats immunized initially with GP-BP in CFA. These data show that ongoing neurologic dysfunction can be induced in the Lewis rat by a GP-BP specific T-lymphocyte line; they suggest that unremitting clinical signs can persist in the absence both of inflammatory lesions in the CNS and of pronounced immunologic responsiveness to the encephalitogenic determinant of GP-BP.     

Increase in anti-astrocyte antibodies in the serum of guinea pigs during active stages of experimental autoimmune encephalomyelitis.

From previous studies on the induction and treatment of experimental autoimmune encephalomyelitis (EAE) in guinea pigs and mice, antibodies have been implicated during both demyelination and remyelination. In the present study, sera from guinea pigs with acute, chronic and myelin basic protein/galactocerebroside (MBP/GC)-treated chronic EAE were evaluated for the presence of anti-glial cell antibodies by immunocytochemical techniques. Antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The majority of sera from acute and chronic active EAE animals displayed intense labelling of astrocytes and only weak staining of oligodendrocytes when tested on sections of normal guinea pig brain tissue. In contrast, sera from animals with chronic EAE treated with MBP/GC gave strong labelling of oligodendrocytes and only minor staining of astrocytes. By immunoblotting, astrocyte staining was shown to be due to the presence of antiglial fibrillary acidic protein (GFAP) antibodies. The intense oligodendrocyte staining observed in sections reacted with sera from MBP/GC-treated guinea pigs corresponded well with high titers of serum anti-GC and anti-MBP antibodies measured by an ELISA. It was concluded that the presence of antibodies against astrocytes was possibly related to astrocytic antigens within the disease-inducing emulsion, at least during the initial phases of EAE, and not to their release from the central nervous system of affected animals.     

Heat shock proteins and experimental autoimmune encephalomyelitis (EAE): I. Immunization with a peptide of the myelin protein 2′,3′ cyclic nucleotide 3′ phosphodiesterase that is cross-reactive with a heat shock protein alters the course of EAE

We describe sequence similarity and immunologic cross-reactivity between a peptide of the mycobacterial hsp, HSP65, and the myelin protein 2′,3′ cyclic nucleotide 3′ phosphodiesterase (CNP). We demonstrate that immunization with the homologous cross-reactive CNP peptide (hsp-CNP peptide) has significant biological consequences. Rats immunized with hsp-CNP peptide in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) produce large amounts of peptide-specific antibody. Isotypes of antibodies in animals immunized with peptide in CFA are IgG1 and IgG2a. Isotypes of antibodies in rats immunized with peptide in IFA are predominantly IgG1, with low titers of IgG2a. T cell proliferative responses to HSP65 are present in rats immunized with peptide in CFA. T cell responses to HSP65 initially are absent in rats immunized with peptide in IFA but develop over time. T cell proliferative responses to hsp-CNP peptide were not detected. None of the groups of rats developed clinical or histologic evidence of experimental autoimmune encephalomyelitis (EAE). To induce EAE, rats preimmunized with hsp-CNP peptide were challenged with guinea pig spinal cord (GPSC) emulsified in CFA. Rats preimmunized with peptide in CFA developed severe EAE. Rats preimmunized with hsp-CNP peptide in IFA were protected from EAE, with both a lower incidence and severity of disease. Injecting the murine monoclonal antibody recognizing the shared HSP65 and CNP epitope did not protect against EAE. Our data suggest that a Th2 pattern of immune response to a CNP peptide that itself is non-encephalitogenic protects against EAE. Immune responses to either hsp or myelin proteins cross-reactive with hsp may play an important role in the development of EAE. © 1996 Wiley-Liss, Inc.     

Analysis of humoral immune responses to LM1 ganglioside in guinea pigs

Guillain-Barré syndrome (GBS) is an autoimmune-mediated disease triggered by a preceding infection. A substantial body of evidence implicates antibodies to various gangliosides in subtypes of GBS. A significant proportion of patients with acute demyelinating subset of GBS have IgG antibodies against peripheral nervous system myelin specific neolactogangliosides such as LM1 and Hex-LM1. Although anti-neolactoganglioside antibodies in GBS were described more than two decades ago, their pathogenic role in neuropathy remains unknown due to the lack of suitable experimental models. In this study, we immunized ten guinea pigs with purified LM1 ganglioside mixed with keyhole limpet hemocyanin (KLH) and emulsified in complete Freund's adjuvant (CFA). Control guinea pigs were injected with KLH emulsified in CFA only. The animals were bled every four week intervals. The animals were boosted 3 times every four weeks. Experiments were terminated four months after initial immunization. Nine of 10 guinea pigs immunized with LM1 exhibited antibody responses to LM1. Anti-LM1 IgG titers in nine guinea pigs ranged from 1:400 to 1:12,800 at 16-weeks after initial immunization. Anti-LM1 antibodies were predominantly of IgG2 subclass. One guinea pig with the highest levels of IgG antibodies exhibited mild signs of neuropathy. There was no evidence of demyelination or inflammation in the sciatic nerves of LM1-immunized guinea pigs. Anti-LM1 antibodies bound to rat sciatic nerve myelin and to isolated rat Schwann cells. In summary, our findings suggest that relatively high levels of anti-LM1 IgG antibodies can be induced in guinea pigs and that LM1 is localized in peripheral nerve myelin and in Schwann cells. Further studies are needed to determine the pathogenic potential of anti-neolactoganglioside antibodies in neuropathy.     

实验性自身免疫性脑脊髓炎大鼠听神经损害研究

目的建立实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)大鼠模型,研究其脑干听觉诱发电位(brainstem auditory evoked potential,BAEP)Ⅰ波和听神经组织学改变。方法40只Wistar大鼠分为实验组和对照组,实验组(EAE组)用含卡介苗的豚鼠全脊髓匀浆为抗原免疫Wistar大鼠建立EAE动物模型,对照组用生理盐水混合完全福氏佐剂注射,采用诱发电位仪检测EAE组急性发病的大鼠和对照组大鼠的BAEP,通过透射电镜观察发病大鼠听神经外周段组织学改变。结果急性发病实验组大鼠BAEP的Ⅰ波潜伏期较对照组显著延长(P<0.01)。透射电镜下观察听神经外周段髓鞘松散,板层分离,局部变薄,呈不完全性脱髓鞘改变,轴突完整。对照组大鼠未见组织学改变。结论急性发病EAE大鼠听神经外周段脱髓鞘可能引起脑干听觉诱发电位Ⅰ波的改变。     

Delayed type skin response to myelin basic protein in chronic relapsing experimental allergic encephalomyelitis

The skin response to myelin basic protein (MBP) was studied in chronic relapsing experimental allergic encephalomyelitis (EAE) using strain 13 guinea pigs. The delayed type skin response showed a monophasic curve; it gradually increased after immunization, reached maximum levels around 80 days post-immunization, and decreased thereafter. Relapses were more frequent while it was at high levels although it did not correlate directly in individuals with the clinical stage. The skin response was also high in MBP-immunized animals which had recovered from acute EAE. Our results suggest that delayed type hypersensitivity to MBP is involved but is not sufficient by itself to cause relapsing EAE.     

Autoimmunity against myelin oligodendrocyte glycoprotein is dispensable for the initiation although essential for the progression of chronic encephalomyelitis in common marmosets

To elucidate the pathogenetic significance of myelin/oligodendrocyte glycoprotein (MOG)-specific autoreactivity in a genetically and immunologically heterogeneous nonhuman primate model of multiple sclerosis, we analyzed experimental autoimmune encephalomyelitis (EAE) in the outbred common marmoset (Callithrix jacchus). One sibling each of 5 bone marrow chimeric marmoset twins was immunized with myelin derived from wild-type (WT) C57BL/6 mice (WT myelin); the other sibling was immunized with myelin from MOG-deficient C57BL/6 mice (MOG -/- myelin). One twin pair developed acute EAE simultaneously; the 4 remaining twin siblings immunized with WT myelin developed chronic progressive EAE, whereas siblings of these 4 monkeys remained free of clinical disease signs. Many EAE-related abnormalities were identified in the CNS of both groups by magnetic resonance imaging and histologic analysis, but mean percentages of spinal cord demyelination were lower in monkeys immunized with MOG -/- myelin (8.2%) than in WT myelin-immunized animals (40.5%). There was a strong correlation between the development of overt clinical EAE and seropositivity for anti-MOG antibodies, but blood and lymph node T-cell proliferative responses showed no relationship to disease. These results indicate that the initiation of CNS inflammation and demyelination can take place in the absence of detectable autoimmunity against MOG, but the clinical progression and histopathologic severity depends on the presence of antibodies against MOG in this multiple sclerosis model.