Effect of geranylgeranylacetone on optic neuritis in experimental autoimmune encephalomyelitis

Optic neuritis is an acute inflammatory demyelinating syndrome of the central nervous system (CNS) that often occurs in multiple sclerosis (MS). Since it can cause irreversible visual loss, especially in the optic-spinal form of MS or neuromyelitis optica (NMO), the present study was conducted to assess the effects of geranylgeranylacetone (GGA) on optic neuritis in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Myelin oligodendrocyte glycoprotein-induced EAE mice received oral administration of GGA at 500 mg/kg or vehicle once daily for 22 days. The effects of GGA on the severity of optic neuritis were examined by morphological analysis on day 22. Visual functions were measured by the multifocal electroretinograms (mfERG). In addition, the effects of GGA on severity of myelitis were monitored both on clinical signs and morphological aspects. The visual function, as assessed by the second-kernel of mfERG, was significantly improved in GGA-treated mice compared with vehicle-treated mice. GGA treatment decreased the number of degenerating axons in the optic nerve and prevented cell loss in the retinal ganglion cell layer. However, the severity of demyelination in the spinal cord remained unaffected with the treatment of GGA. These results suggest that oral GGA administration has beneficial effect on the treatment for optic neuritis in the EAE mouse model of MS.     

Eotaxin-2 blockade ameliorates experimental autoimmune encephalomyelitis

AIM: To study the effect of blocking the eo-2 pathway on the development and severity of experimental autoimmune encephalomyelitis (EAE). METHODS: We produced mAb directed against eo-2, named D8. MOG35-55 induced-EAE mice were daily intravenously injected with either 25 μg or 100 μg D8, or with vehicle control alone [phosphate-buffered saline (PBS)], starting from day 0 post immunization and were monitored for EAE clinical score (n = 10 in each group). Mice were sacrificed on day 58 and their sera were assessed for the presence of anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies autoantibodies, as well as for the profile of pro-inflammatory cytokines and chemokines. Histological analysis of brain sections was performed by hematoxylin and eosin staining. RESULTS: Daily treatment of EAE induced mice with D8 significantly decreased the severity of EAE symptoms. Treatment with both concentrations of D8 ameliorated EAE symptoms compared to PBS treated mice, starting from day 42 post immunization (0.89 ± 0.35 in D8 25 μg and D8 100 μg treated groups vs 2.11 ± 0.38 in the PBS treated group, P = 0.03). A significant improvement in EAE clinical score compared to total IgG treated mice was observed with the higher concentration of D8 (0.81 ± 0.38 in D8 100 μg treated group vs 2.11 ± 0.31 in IgG1 treated group, on day 56 post immunization, P = 0.04). D8 treated mice with EAE did not significantly exhibit lower sera levels of anti-MOG autoantibodies compared to IgG-treated mice. However, they expressed lower sera levels of the pro-inflammatory cytokines: tumor necrosis factor (7.8 ± 0.2 pg/mL in D8 100 μg treated mice vs 19.9 ± 3.4 pg/mL in IgG treated mice, P = 0.005) and interferon-gamma (1.4 ± 0.6 pg/mL in D8 100 μg treated mice vs 3.6 ± 0.4 pg/mL in IgG treated mice, P = 0.02), as well as reduced levels of the chemokine macrophage chemoattractant protein-1 (27.2 ± 3.1 pg/mL in D8 100 μg treated mice vs 63.7 ± 12.3 pg/mL in IgG treated mice, P = 0.03). These findings indicate that blocking the eo-2 pathway in EAE may affect not only eosinophil infiltration into the central nervous system (CNS), but also have an effect on monocytes and T cells, but not humoral, mediated responses. Histological analysis of the brains of D8 treated mice with EAE support that this treatment decreases immune cells infiltrates in the CNS. CONCLUSION: Taken together, these findings suggest a role for eo-2 in EAE pathogenesis and consequentially may support a therapeutic potential of anti-eo-2 neutralizing mAb in multiple sclerosis.     

Th1‐mediated experimental autoimmune encephalomyelitis is CXCR3 independent

Drugs that block leukocyte trafficking ameliorate multiple sclerosis (MS). Occurrences of opportunistic infection, however, highlight the need for novel drugs that modulate more restricted subsets of T cells. In this context, chemokines and their receptors are attractive therapeutic targets. CXCR3, a Th1‐associated chemokine receptor, is preferentially expressed on T cells that accumulate in MS lesions and central nervous system (CNS) infiltrates of mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice genetically deficient in either CXCR3 or CXCL10 succumb to EAE following active immunization with myelin antigens. EAE is mediated by a heterogeneous population of T cells in myelin‐immunized mice. Hence, disease might develop in the absence of CXCR3 secondary to the compensatory action of encephalitogenic CCR6⁺ Th17 cells. However, in the current study, we show for the first time that blockade or genetic deficiency of either CXCR3 or of its primary ligand has no impact on clinical EAE induced by the adoptive transfer of highly polarized Th1 effector cells. Our data illustrate the fact that, although highly targeted immunotherapies might have more favorable side effect profiles, they are also more likely to be rendered ineffective by inherent redundancies in chemokine and cytokine networks that arise at sites of neuroinflammation.     

实验性自身免疫性脑脊髓炎小鼠发病高峰期外周及中枢淋巴细胞亚群的变化

目的:观察髓鞘少突胶质细胞糖蛋白MOG35-55诱导的实验性自身免疫性脑脊髓炎小鼠发病高峰期中枢及外周淋巴细胞亚群的变化,探讨EAE发病高峰期细胞与体液免疫学的变化。方法:用MOG35-55免疫诱导雌性C57BL/6小鼠制作EAE模型,记录小鼠行为学变化,HE染色观察CNS炎症组织病理变化,使用流式细胞仪检测小鼠中枢及外周脾脏淋巴细胞中CD3+CD4+、CD3+CD8+、CD4+CD25+、B220+细胞亚群变化情况。结果:EAE组小鼠中枢神经系统有CD3+CD4+、CD3+CD8+、CD4+CD25+、B220+淋巴细胞的浸润,CFA阴性对照组中枢神经系统未检测到淋巴细胞浸润。EAE组小鼠外周脾细胞中CD3+CD4+、CD3+CD8+细胞较CFA阴性对照组减少(P0.05),B220+细胞较CFA阴性对照组明显升高(P0.01),CD4+CD25+细胞较CFA阴性对照组升高但无统计学差异。结论:小鼠在EAE发病高峰期,外周脾细胞中CD3+CD4+、CD3+CD8+阳性细胞明显减少,B220+明显升高,CD4+CD25+也开始有升高趋势,表明EAE发病高峰期细胞免疫及体液免疫共同调控了EAE的病理过程,T淋巴细胞与B淋巴细胞都起了很重要的主导作用。     

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.     

Antigen-driven tissue-specific suppression following oral tolerance: Orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse

Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-β after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.     

A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: Fine specificity and T cell receptor Vβ expression of encephalitogenic T cells

A predominant response to myelin oligodendrocyte glycoprotein (MOG) was recently observed in patients with multiple sclerosis (MS). To study the possible pathogenic role of T cell response to MOG in MS, we have investigated the encephalitogenic potential of MOG. Synthetic MOG peptides, pMOG 1-21, 35–55, 67–87, 104–117 and 202–218, representing predicted T cell epitopes, were injected into C57BL/6J and C3H.SW (H-2^b) mice. The mice developed significant specific T cell responses to pMOG 1–21, pMOG 35–55 and pMOG 104–117. However, pMOG 35–55 was the only MOG peptide which could induce neurological impairment. The highly reproducible disease was chronic, with ascending paralysis and neuropathology comparable with those observed in experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein or proteolipid protein, except that in H-2^b mice the disease was consistently non-remitting. These features differ markedly from those which we recently observed in PL (H-2^u) mice with pMOG 35–55-induced disease. In PL mice, pMOG 35–55-induces atypical chronic relapsing EAE, the expression and progression of which are unpredictable. Hence, in different mouse strains, the same MOG peptide can induce typical EAE characterized by ascending paralysis, or atypical EAE with unpredictable clinical signs. pMOG 35–55-specific T cells from H-2^b mice recognized an epitope within amino acids 40–55 of the MOG molecule, and pMOG 40–55-reactive T cell lines were encephalitogenic upon transfer into syngeneic recipients. The encephalitogenic pMOG 35–55-reactive C57BL/6J T cell lines expressed Vβ1, Vβ6, Vβ8, Vβ14 and Vβ15 gene segments, and the pMOG 35–55-reactive C3H.SW T cell lines expressed Vβ1, Vβ2, Vβ6, Vβ8, Vβ10, Vβ14, and Vβ15 gene segments. However, in both mouse strains, the utilization of the Vβ8 gene product was predominant (40–43 %). The highly reproducible encephalitogenic activity of pMOG 35–55 strongly suggests a pathogenic role for T cell reactivity to MOG in MS and supports the possibility that MOG may also be a primary target antigen in the disease.     

细胞因子在实验性自身免疫性脑脊髓炎耐受中的作用

细胞因子(CK)在实验性自身免疫性脑脊髓炎(EAE)的免疫机制中起着重要作用。Th细胞的不同转化决定EAE的发生、发展或抑制。由多种CK构成的免疫调节网络操纵着Th细胞的免疫应答。通过作用Th细胞使之向抑制EAE方向转化,从而寻找对EAE耐受的途径,是目前EAE研究的一个重要方面。以下就与EAE耐受相关的CK研究进行综述,探讨EAE免疫病理机制。     

Chronic relapsing experimental autoimmune encephalomyelitis with a delayed onset and an atypical clinical course,induced in PL/J mice by myelin oligodendrocyte glycoprotein (MOG)-derived peptide: Preliminary analysis of MOG T cell epitopes

Myelin basic protein (MBP) and proteolipid protein (PLP), the most abundant proteins of central nervous system (CNS) myelin, have been extensively studied as possible primary target antigens in multiple sclerosis (MS), a primary demyelinating autoimmune disease of the CNS. However, there is increasing evidence to suggest that autoimmune reactivity against the quantitatively minor myelin component, myelin oligodendrocyte glycoprotein (MOG), can also play a role in the pathogenicity of MS. We recently demonstrated a predominant response to MOG by peripheral blood lymphocytes from patients with MS tested for their reactivity against various myelin antigens, including MBP and PLP. To ascertain whether or not T cell reactivity to MOG in MS is a potentially pathogenic response, we have tested the ability of synthetic MOG peptides (pMOG) representing potential T cell epitopes, to induce neurological disease in mice. Both strains of mice tested (SJL/J and PL/J mice) were able to mount a primary T cell response to some of the five MOG peptides synthesized, pMOG 1–21, 35–55, 67–87, 104–117 and 202–218. T cell lines could be raised in both strains to pMOG 35–55 and 67–87, but epitope definition revealed that each strain recognized a different minimal epitope within these two peptides. T cell lines to pMOG 1–21 and 202–218 could also be raised in SJL/J and PL/J mice, respectively. T cell reactivity to pMOG 104–117 was not observed in either mouse strain. None of the peptides tested induced detectable clinical signs in SJL/J mice. In contrast, an MS-like chronic relasping-remitting disease could be induced in PL/J mice with pMOG 35–55. The disease presented with a delayed onset and with clinical signs which differed significantly in their progression and expression from the typical ascending paralysis of experimental autoimmune encephalomyelitis induced with other myelin components, such as MBP and PLP. Histological examination of CNS tissue from mice injected with pMOG 35–55 revealed only mild neuropathological signs with few inflammatory foci in brain and spinal cord. Some myelin splitting and edema were detected upon electron microscopic examination in the spinal cord and cerebellum. Transfer of pMOG 35–55 reactive T cells into naive PL/J mice resulted in pathological changes characterized by inflammatory foci in the brain and spinal cord. This passively induced disease was clinically silent, as was also reported for Lewis rats injected with T cells specific for the same MOG peptide. These data, which demonstrate unequivocally the encephalitogenic activity of MOG, support our contention that MOG may be as important as MBP or PLP in disease pathogenesis and could be a primary target antigen in autoimmune diseases of the CNS.     

Orally administered myelin basic protein in neonates primes for immune responses and enhances experimental autoimmune encephalomyelitis in adult animals

Antigen-driven tolerance is an effective method for suppression of autoimmune diseases. Adult animals can be tolerized against the induction of experimental autoimmune encephalomyelitis (EAE) by both oral and parenteral administration of myelin basic protein (MBP). We have found that in contrast to previous studies of neonatal tolerance in which parenterally administered autoantigens induced tolerance, the oral administration of MBP in neonatal rats did not result in tolerization to MBP, but instead, primed for immunologic responses. Proliferative responses to MBP and its encephalitogenic epitope were present in animals fed with MBP as neonates and co-culture of encephalitogenic T cells with cells from neonatal rats fed with MBP were associated with enhanced MBP responses rather than the suppression observed with cells from adult rats fed with MBP. Furthermore, neonates fed with MBP and immunized 6–8 weeks later with MBP in adjuvant to induce EAE revealed enhancement of disease severity, and were not protected from a second attack upon active reinduction of EAE. Subcutaneous injection of soluble MBP into neonates had no effect on EAE induction as adults, whereas intraperitoneal injection of MBP in neonates was associated with marked suppression of disease in adults. Suppression of EAE began to appear in animals fed with MBP at 4 weeks of age, and was similar to oral tolerance in adult animals when animals were fed at 6 weeks of age. These results suggest that immaturity of the immunoregulatory network associated with oral tolerance and sensitization to autoantigens via the gut in the neonatal period may contribute to the pathogenesis of autoimmune diseases.     

Monoclonal antibody therapy in experimental allergic encephalomyelitis and multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated demyelinating disease of the central nervous system that has been used as an animal model for multiple sclerosis (MS). Based on the exciting results in EAE, a number of novel immunotherapies employing biotechnological products, rather than conventional immunosuppressants, are being developed for the treatment of MS. In this review, we delineate the rationale for monoclonal antibody (MAb) therapy in EAE and MS and summarize the various levels at which immune intervention was performed. For each approach, we discuss the role of MAbs at the level of lymphocyte and cytokine networks, chemokines, and adhesion molecules or their receptors.     

Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis

Triggering receptor expressed on myeloid cells (TREM-2) is a membrane receptor associated with DAP12 that is expressed primarily in myeloid cells, including dendritic cells and microglia, and promotes fusion of osteoclast precursors into multinucleated cells. A rare autosomal recessive condition, Nasu-Hakola disease (NHD) is associated with loss-of-function mutations in DAP12 and TREM-2. The brain pathology observed in NHD patients suggests that disruption of the TREM-2/DAP12 pathway leads to neurodegeneration with demyelination and axonal loss. In this study, we have characterized TREM-2 protein expression on microglia using a newly produced monoclonal antibody directed against the mouse TREM-2 receptor. We report that TREM-2 expression is up-regulated in the spinal cord during both the early inflammatory and chronic phases of myelin oligodendrocyte glycoprotein (MOG)(35-55)peptide-induced experimental autoimmune encaphalomyelitis (EAE). We also demonstrate that TREM-2 is highly expressed on microglial cells in the central nervous system (CNS) during EAE and that blockade of TREM-2 during the effector phase of EAE results in disease exacerbation with more diffuse CNS inflammatory infiltrates and demyelination in the brain parenchyma. These results demonstrate a critical role for TREM-2 during inflammatory responses in the CNS.     

降纤药治疗实验性自身免疫性脑脊髓炎小鼠的机制

目的:研究降纤药巴曲酶对实验性自身免疫性脑脊髓炎(EAE)小鼠的预防及治疗作用,初步探讨纤维蛋白沉积在多发性硬化(MS)中的作用机制。方法:采用MOG35-55免疫的C57雌性小鼠,诱发EAE动物模型,分别在免疫后立即(预防组)及免疫后出现症状(治疗组)隔日连续给予降纤药巴曲酶注射至实验结束,观察发病情况并进行临床症状评分。于免疫后30天、40天及60天分别将预防组、治疗组及EAE对照组小鼠脊髓与小脑组织取材后进行组织病理学与免疫组化染色分析,Western blot及实时荧光定量PCR技术观察药物干预对炎性浸润、脱髓鞘、纤维蛋白沉积及胶质细胞活化的影响。结果:降纤预防组及治疗组均可明显减轻EAE小鼠的发病症状、降低临床评分。预防组和治疗组较EAE未用药对照组小鼠炎性细胞浸润明显减少、髓鞘脱失及胶质细胞活化减轻,但轴索损害的改善作用不明显。免疫组化及免疫荧光显示,预防组和治疗组较EAE未用药对照组的髓鞘碱性蛋白(MBP)表达升高而胶质纤维酸性蛋白(GFAP)表达降低,Western blot结果示MBP蛋白表达升高而p-Akt表达降低。实时荧光定量PCR技术也证实了预防及治疗组MBP的mRNA表达升高,组织型纤溶酶原激活物(-tPA)的mRNA表达也升高。结论:在EAE的发病过程中纤维蛋白沉积发挥了重要作用,巴曲酶通过有效降低EAE小鼠体内的纤维蛋白从多个方面改善临床症状和发病过程。     

Edaravone, a free radical scavenger, ameliorates experimental autoimmune encephalomyelitis

Reactive oxygen species (ROS) are implicated in the pathogenesis of multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE). The effect of edaravone, a free radical scavenger, on EAE was investigated in this study. Treatment with edaravone significantly ameliorated the clinical severity of EAE, and a reduced infiltration of lymphocytes was observed based on a histological analysis. The expression of inducible NO synthase (iNOS) in the spinal cords appeared to be reduced by the treatment with edaravone and this effect was confirmed in vitro. A reduction of both the cellular infiltration and the expression of iNOS may therefore underlie the mechanisms of the beneficial effect of edaravone on EAE.     

Peptide-based immunotherapy of experimental autoimmune encephalomyelitis without anaphylaxis

Administration of peptide antigens in tolerogenic form holds promise as a specific treatment for autoimmune and allergic disorders. However, experiments in rodent autoimmune models have highlighted the risk of anaphylaxis in response to systemic peptide application once the aberrant immune response is underway. Thus, mice with clinical signs of experimental autoimmune encephalomyelitis (EAE) or diabetes have been reported to suffer fatal anaphylaxis upon administration of native autoantigenic peptides. Clearly, this might represent a significant barrier to the use of synthetic peptides in the treatment of ongoing human autoimmune conditions. Here we describe the development of an altered peptide ligand (APL) engineered to prevent anaphylaxis (no antibody binding) whilst retaining the ability to silence pathogenic myelin-reactive T lymphocytes. Administration of the APL to mice with an ongoing anti-myelin immune response did not cause anaphylaxis, but led to complete protection from the subsequent induction of EAE and, when given during ongoing EAE, led to a rapid remission of clinical signs. The approach of removing antibody recognition whilst maintaining the desired functional effect (in this case T cell tolerance) may be of value in other situations in which there is a risk of triggering anaphylaxis with peptide-based drugs.     

Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice

The encephalitogenic peptide pMOG 35 – 55 from the myelin oligodendrocyte glycoprotein was used to induce experimental autoimmune encephalomyelitis (EAE) in H-2^b mice with the interleukin-6 (IL-6) gene intact or disrupted. The IL-6^+/+ mice developed a chronic form of EAE ascending paralysis, whereas the IL-6^−/− mice were resistant to the disease. Injections of recombinant IL-6 following pMOG immunization induced severe disease in the IL-6^−/− mice. Histological examination of brain and spinal cord sections showed that the perivascular infiltration of inflammatory cells evident in IL-6^+/+ mice was absent in the IL-6^−/− animals and could be restored by exogenous IL-6 administration. Anti-MOG antibody levels were much lower in the IL-6^−/− mice, but were not restored to high levels by IL-6 injections which elicited the development of pMOG 35 – 55-induced EAE. T lymphocytes reactive to the pMOG antigen were recovered from lymph nodes of both types of mice and T cell lines could be established from both. Adoptive transfer of T cell lines from IL-6^+/+ mice induced EAE in the mice with the intact IL-6 gene but less in the IL-6-deficient mice, indicating that the resistant phenotype cannot be explained solely by lack of encephalitogenic T cells. The absence of cell infiltrates in the brain and spinal cords of IL-6^−/− mice upon adoptive transfer of the pathogenic T cells from IL-6^+/+ mice is consistent with a function of IL-6 in the local perivascular inflammatory process.     

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self‐antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4⁺ T cells that secrete interleukin (IL)‐17, termed Th17, but also IL‐17‐secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL‐17‐producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8⁺ and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.