Passive transfer of experimental allergic encephalomyelitis induced by proteolipid apoprotein

In an attempt to obtain insight into the pathogenesis of proteolipid apoprotein (PLP)-induced experimental allergic encephalomyelitis (EAE) in Lewis rats (Yamamura et al. 1986), PLP-sensitized lymph node cells or spleen cells were passively transferred into normal or irradiated (400 rad) recipients after incubation with concanavalin A or PLP. Clinical EAE manifested by paraparesis was successfully transferred into irradiated recipients with 2 - 2.5 X 10(8) of the primary cultured cells and histologic EAE could be transferred with as few as 5 X 10(7) cells into naive recipients. This is the first demonstration of passive EAE induced with PLP-sensitized lymphoid cells and suggests the pathogenetic importance of cell-mediated immunity to PLP.     

Sequence 104–117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice

Immunization of animals with myelin proteolipid protein (PLP) causes experimental autoimmune encephalomyelitis (EAE), a disease model that shares many features with human multiple sclerosis (MS). The SJL/J (H-2⁵) mouse is widely used in EAE studies because of its high disease susceptibility. Previous studies have shown that sequences 139–151 HCLGKWLGHPDKF and 178–191 NTWTTCQSIAFPSK represent distinct co-immunodominant encephalitogenic determinants of PLP for SJL/J mice. In the present study, we identify a third distinct PLP encephalitogenic peptide for SJL/J mice. Following immunization with PLP 104–117 KTTICGKGLSATVT, 10/14 SJL/J mice developed clinical and histological EAE with a mean time of onset of 38 days (18–65 days). T cell lines generated from SJL/J mice immunized with p104–117 were predominantly (> 90%) CD3⁺, CD4⁺, αβTCR⁺, CD8^dim, γδTCR^dim T cells and responded in an Ag-specific, I-As-restricted manner to p104–117. Upon adoptive transfer of 16−40 × 10⁶ T line cells, EAE was produced in naive SJL/J recipients 20–34 days after transfer. The delayed onset of both active and passive disease may be related to the non-immunodominant, cryptic nature of p104–117 in SJL/J mice. Lymph node cells from SJL/J mice immunized with either whole PLP or with pooled encephalitogenic PLP peptides responded to challenge with the immunodominant PLP determinants p139–151 and p178–191 but did not respond to p104–117. The existence of three distinct PLP encephalitogenic T cell determinants for SJL/J mice suggests that susceptibility to EAE and perhaps MS may be related to promiscuous T cell recognition of multiple myelin protein determinants.     

An α-chain TCR CDR3 peptide can enhance EAE induced by myelin basic protein or proteolipid protein

Regulation of experimental autoimmune encephalomyelitis (EAE) can be induced by anti-idiotype immunity against T cell receptor (TCR) fragments associated with major histocompatibility complex (MHC) molecules. However, we have recently found that preimmunization with an α-chain TCR CDR3 peptide (LYFCAARSNYQL) derived from myelin basic protein (MBP)-specific clones did not suppress but rather augmented the severity of EAE induced by MBP-specific T cells in SJL/J mice. To test whether CDR3 vaccination could control only a highly restricted T cell population, we studied the effect of the peptide against EAE induced by T cells specific for different Ag/MHC ligands and autoimmune diseases affecting non-neural tissues. In contrast to expectations, the peptide was found to augment not only EAE induced by MBP-specific T cells, but also proteolipid protein (PLP)-specific T cell- or PLP peptide-induced EAE in SJL/J mice, and MBP-induced EAE and adjuvant arthritis (AA) in rats. The CDR3 peptide was neither inhibitory nor supportive for Ag-induced activation of an encephalitogenic clone in vitro. In addition, the peptide treatment neither inhibited the induction of Ag-specific T cells nor altered the APC function of spleen cells. These findings, on the one hand, confirm previous results showing TCR peptide-induced enhancement of the disease and, on the other hand, indicate that the TCR CDR3 peptide may control T cells with broader Ag/MHC specificities than could be expected. Structural similarity among TCR idiotypes of autoimmune T cells may partly account for these results. © 1996 Wiley-Liss, Inc.     

Encephalitogenic T lymphocytes develop from SJL/J hematopoietic cells transplanted into severe combined immimodeficient ( SCID) mice

Previously, we constructed chimeras by injecting hematopoietic cells from experimental autoimmune encephalomyelitis (EAE)-susceptible SJL (H-2^S) strain mice into severe combined immunodeficient (SCID) C.B-17scid /scid (H-2^d) mice. These SCID mouse-SJL mouse hematopoietic cell chimeras developed passive EAE following adoptive transfer of PLP S139–151-specific SJL T lymphocyte line cells, but were resistant to active EAE induced by primary immunization with PLP S139–151. In order to gain an understanding of the encephalitogenic potential of transplanted hematopoietic progenitors in SCID mouse-SJL mouse chimeras, we attempted to induce EAE in hematopoietic chimeras constructed with or without an additional SJL fetal thymus implant. Chimeras with the thymus implant were susceptible to passive and active EAE while chimeras without the thymus implant were susceptible to passive but not active EAE. Encephalitogenic, CD4⁺, TCR⁺ T lymphocytes were selected in vitro from PLP S139-151-immunized, thymus-implanted chimeras. These results showed that hematopoietic SJL progenitors developed into antigen-presenting accessory cells and immunocompetent encephalitogenic T lymphocytes following transplantation into SCID mice. The development of primary immune reactivity depended on a fetal thymus implant for expression in SCID mouse-SJL mouse chimeras.     

Lack of H-2 restriction of suppressor factor specific to myelin basic encephalitogen

A cell-free extract has been prepared from spleen cells of (SJL/J x BALB/c)F1 mice which were rendered non-susceptible to EAE by treatment with mouse spinal cord homogenate in incomplete Freund's adjuvant. Such extract has been previously shown to have suppressive activity on the induction of EAE, as well as on the immune response in syngeneic mice towards the mouse basic protein. We have now demonstrated that this factor is as effective in several other strains of mice, of different H-2 haplotype. The activity of this factor was manifested both in vivo by inhibiting the DTH response to MBE in the various mouse strains, and in vitro, by blocking the MIF activity of the allogeneic lymphocytes. A suppressor factor was prepared by a similar procedure from the EAE-resistant BALB/c mice. This factor was as active as the factor from the (SJL/J x BALB/c)F1 hybrid in blocking the anti-MBE antibody binding to MBE. It is also suppressive, and it inhibited the DTH response to MBE in both syngeneic and semi-allogeneic (SJL/J x BALB/c)F1 mice. It is thus demonstrated that the MBE-specific soluble suppressor factor involved in the EAE system in mice shows no indication of H-2 restriction.     

Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein.

Proteolipid protein (PLP) is a major component of the central nervous system (CNS) myelin membrane and has been shown to induce acute experimental autoimmune encephalomyelitis (EAE) in genetically susceptible animals. Here we describe conditions by which a relapsing-remitting form of EAE can be reliably induced in SJL/J mice either actively immunized with the major encephalitogenic PLP peptide, PLP13-151(S), or following adoptive transfer of PLP139-151(S)-specific T cells. The disease follows a reliable relapsing-remitting course with acute clinical signs first appearing 6-20 days after priming or transfer and relapses first appearing at 30-45 days. The initial onset of disease correlates with delayed-type hypersensitivity (DTH) reactivity specific for PLP139-151(S), in the apparent absence of T cell reactivity to the major myelin basic protein (MBP) peptide. Histologically, both the active and adoptive forms of the disease are characterized by extensive mononuclear cell infiltration and severe demyelination of the CNS. These results suggest that T cell responses specific for PLP139-151(S) are sufficient to induce clinical and histological R-EAE in SJL/J mice. This model should prove useful for examination of the cellular and molecular events involved in clinical relapses and perhaps in determining the role of PLP-specific T cell responses in multiple sclerosis (MS).     

Treatment of relapsing experimental autoimmune encephalomyelitis with T cell receptor peptides

Restricted T cell receptor (TCR) VB gene usage by T cells for recognition of antigens involved in the production of experimental autoimmune encephalomyelitis (EAE) offers the possibility of selective immunotherapy. We determined the preferential VB gene usage of lymph node-derived clones from SJL/J mice to recognize the encephalitogenic epitope PLP 139-151 and from PL/J mice to recognize the newly described encephalitogenic epitope PLP 43-64. In addition, the VB gene usage for recognition of PLP 139-151 by T cell lines derived from SJL/J spinal cords was analyzed. Lymph node-derived SJL/J lines and clones specific for PLP 139-151 expressed VB2, VB4, and VB17a preferentially, and PL/J lines and clones specific for PLP 43-64 expressed VB2 and VB8.2 preferentially. A VB4+ SJL/J clone and a VB8.2+ PL/J clone were encephalitogenic. Encephalitogenic SJL/J lines derived from spinal cord expressed VB2, VB10, VB16, and VB17a preferentially, with a predominance of VB2. Candidate TCR peptides were synthesized and tested from the VB gene families VB4, VB8.2, and VB17a, based on our data and previous data on BP-induced EAE in mice. Treatment of relapsing EAE (R-EAE) in SJL/J mice with VB4 and VB17a peptides reduced clinical and histological disease severity, and treatment of R-EAE in (PLxSJL)F1 mice with VB4 and VB8.2 peptides also reduced clinical and histological disease. The use of TCR peptide therapy may have applications for the treatment of human autoimmune diseases such as multiple sclerosis. © 1993 Wiley-Liss, Inc.     

Gender differences in experimental autoimmune encephalomyelitis develop during the induction of the immune response to encephalitogenic peptides

Multiple sclerosis (MS) strikes women more often than men. Gender differences in experimental autoimmune encephalomyelitis (EAE) parallel those seen in MS. We utilized the adoptive transfer model of EAE to determine the role of gender on the induction and effector phases of disease. PLP 139–151-sensitized spleen cells from female SJL mice were more effective at transferring disease than male cells. However, there were no gender differences in the frequency of PLP 139–151-specific T cells. PLP 139–151-specific female T cell lines induced more severe disease than male T cell lines. Disease severity was more strongly linked to the sex of the donor T cells, indicating that gender influences the immune response primarily during the induction phase. J. Neurosci. Res. 52:420–426, 1998. © 1998 Wiley-Liss, Inc.     

Treatment of relapsing autoimmune encephalomyelitis with T cell receptor Vβ-specific antibodies when proteolipid protein is the autoantigen

Monoclonal antibodies (mAbs) directed against the Vβ chain of the T cell receptor (TCR) of pathogenic T cells have been used to treat acute murine experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (BP). We evaluated anti-Vβ mAb for the treatment of relapsing EAE (R-EAE) induced in SJL/J mice by the myelin proteolipid protein (PLP) peptide 139–151. Spinal cord mononuclear cells isolated from mice immunized for R-EAE with PLP 139–151 were shown to express a predominance of Vβ2 and Vβ17 during acute and relapsing disease. T cell lines specific for PLP 139–151 were magnetically sorted to express 80–90% Vβ2. These Vβ2-enriched lines induced typical relapsing demyelinating EAE in naive recipient mice. SJL/J mice with R-EAE induced by a PLP 139–151-specific T cell line expressing 88% Vβ2 were treated with anti-Vβ2 mAb. Anti-Vβ2 mAb markedly reduced clinical and histological disease severity when given at the time of cell transfer or when given at clinical disease onset. In contrast, anti-Vβ mAbs showed only a mild clinical effect on R-EAE induced by immunization with PLP 139–151 or R-EAE induced by immunization with PLP 139–151 or R-EAE transferred by a PLP 139–151-specific T cell line expressing multiple Vβs. A cocktail of mAbs directed against Vβ2, Vβ4, and Vβ17 significantly reduced the numbers of spinal cord T cells expressing these Vβs during acute EAE but had little effect on disease course, suggesting that pathogenic T cells expressing other Vβs were producing disease. These findings may have implications for the treatment of multiple sclerosis with Vβ-selective therapy. © 1996 Wiley-Liss, Inc.     

Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes

Injection of antigen cross-linked accessory cells has proven to be an efficient and highly selective approach for inducing epitope-specific peripheral tolerance. This approach has been used successfully to inhibit induction of experimental autoimmune encephalomyelitis (EAE) and to dissect the relative dominance of component encephalitogenic determinants that contribute to both acute and relapsing EAE. In this study, we evaluated the tolerogenic effect of the dominant encephalitogenic epitope for SJL/J mice, residues 139–151 of myelin proteolipid protein (PLP), on the induction and relapses of EAE induced actively with PLP139-151/CFA. Our results demonstrate the powerful protective effect of treating mice before induction of EAE with PLP139–151-conjugated splenocytes (SPL) on the incidence and severity of both the initial episode and the first relapse of EAE. Moreover, treatment of mice on the first day of onset of clinical signs of EAE reduced the severity of the first relapse, apparently by reducing T cell recognition of PLP139–151, although no significant therapeutic effect was observed during the initial treated clinical episode. These data demonstrate the utility of using neuroantigen-coupled accessory cells to prevent and treat relapsing EAE. © 1996 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Production of experimental allergic encephalomyelitis with the aid of pertussigen in mouse strains considered genetically resistant

Strains of mice (BALB/c An Bradley/Wehi, C57B1/10J, CBA/ca H Wehi, DBA/2 Wf, A/J Wehi), thought to be genetically resistant to experimental allergic encephalomyelitis (EAE) and known to be resistant to becoming hypersensitive to histamine after administration of pertussis vaccine were tested for their ability to develop EAE when purified pertussigen was included in the immunization. It was found that C57B1/10J, CBA/ca H Wehi, BALB/c An Bradley/Wehi and DBA/2 Wf developed typical signs and histologic evidence of EAE. The A/J Wehi and the B10D2/n Sn (not previously tested) strains developed only mild signs of EAE, while the known susceptible (SJL/J X BALB/c An Bradley/Wehi) F1 hybrids developed severe EAE. Histologic evidence of EAE was lacking in A/J Wehi mice and was minimal in B10D2/n Sn mice. These results suggest that neither the H-2 complex nor the gene controlling susceptibility to sensitization to histamine by administration of pertussigen are wholly responsible for susceptibility to EAE.     

Enhanced response to antigen within lymph nodes of SJL/J mice that were protected against experimental allergic encephalomyelitis by T cell vaccination

The effects of T cell vaccination on peripheral immune responsiveness are not yet fully understood. We have induced resistance to rat spinal cord homogenate (RSCH)-induced experimental allergic encephalomyelitis (EAE) in SJL/J mice by vaccination with four T cell lines (RZ8, RZ15, RZ16, and A51) which were reactive to myelin basic protein (MBP) but not to proteolipid protein (PLP). The effect was relatively neuroantigen-specific since vaccination with ovalbumin (OVA)-reactive and alloantigen-specific cells did not prevent EAE induction. Alloantigen-reactive cells reduced the rate of relapse. The number of central nervous system (CNS) infiltrates and mean clinical EAE scores were significantly reduced. This is the first report demonstrating T cell vaccination in the SJL/J mouse, a strain in which PLP is the predominant encephalitogen in RSCH. The vaccinating cells were of the memory/effector (CD44^high, CD45RB^low) surface phenotype. We examined the effect of T cell vaccination on lymph node T cell proliferative responses to MBP, encephalitogenic peptides of PLP and MBP, OVA and anti-CD3. With the exception of polyclonal cytokine responses to anti-CD3, which remained unchanged, vaccination led to a 5–10-fold augmentation in all, including background, responses. By comparison with lymph node cell (LNC) responses from naive mice and mice primed with OVA, it appeared that T cell vaccination restored cellular activation levels which had been depleted in peripheral lymphoid tissues of unvaccinated animals with EAE.     

Myelin proteolipid protein: minimum sequence requirements for active induction of autoimmune encephalomyelitis in SWR/J and SJL/J mice

Proteolipid protein (PLP) is the major protein constituent of mammalian central nervous system myelin. We have previously identified two different PLP encephalitogenic T cell epitopes in two mouse strains. Murine PLP peptides 103-116 YKTTICGKGLSATV and 139-151 HCLGKWLGHPDKF are encephalitogenic determinants in SWR/J (H-2q) and SJL/J (H-2s) mice, respectively. The purpose of the present study was to determine the minimum sequence requirements for each of these PLP encephalitogens. In SWR/J mice, at least two distinct overlapping peptides can induce experimental autoimmune encephalomyelitis (EAE). The eleven residue sequences PLP 105-115 TTICGKGLSAT and PLP 106-116 TICGKGLSATV are encephalitogenic in SWR/J mice, but PLP 106-115 TICGKGLSAT, the decapeptide indigenous to both sequences, is non-encephalitogenic. In contrast, the shortest PLP sequence capable of inducing EAE in SJL/J mice is the nonapeptide 141-149 LGKWLGHPD. These data indicate that encephalitogenic determinants of PLP are short contiguous peptide sequences similar in length and diversity to those of MBP.     

Anti-tumor necrosis factor therapy abrogates autoimmune demyelination.

To define a role for the cytokine tumor necrosis factor (TNF) in immune-mediated demyelination, the effect of anti-TNF antibody was investigated with a form of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice induced by the adoptive transfer of myelin basic protein-(MBP)-sensitized T lymphocytes, an animal model of the human disease multiple sclerosis (MS). In three separate experiments, no mouse sensitized for EAE and then treated with anti-TNF by intraperitoneal injection developed signs of central nervous system (CNS) disease. Examination of CNS tissue from anti-TNF-treated animals showed no pathological changes. CNS tissue from control animals demonstrated extensive inflammatory cell infiltration and demyelination. To test whether anti-TNF therapy was inhibitory to encephalitogenic cells, preincubation of MBP-sensitized T lymphocytes with anti-TNF in vitro prior to injection into recipient mice was performed, and resulted in no diminution of their ability to transfer EAE. In addition, spleen cells from anti-TNF-treated mice were capable of serial transfer of EAE, similar to spleen cells from control animals. However, spleen cells from anti-TNF-treated mice did not produce TNF on stimulation with MBP or concanavalin A. This study showed that anti-TNF antibody can inhibit effectively the development of EAE by interfering with the effector, rather than the induction, phase of the disease. Anticytokine therapy may have important applications in the development of new therapeutic strategies for MS.     

Experimental allergic encephalomyelitis in susceptible and resistant strains of mice after adoptive transfer of T cells activated by antibodies to the T cell receptor complex.

Lymphoid cells from normal and myelin basic protein (MBP)-immune PL/J, SJL/J and (SJL x PL)F1 hybrid mice were activated by in vitro culture with monoclonal antibodies specific for CD3 or specific T cell receptor (TCR) V beta chains. Lymphoid cells activated in this manner from MBP-immune animals did not readily transfer experimental acute encephalomyelitis (EAE) to naive syngeneic recipients in contrast to lymphoid cells from the same source cultured with concanavalin A (ConA) or myelin basic protein (MBP). However, recipients of anti-TCR antibody-activated MBP-specific blasts showed accelerated onset and increased severity of EAE following immunization with MBP as compared to unmanipulated control animals. Anti-TCR activated cells incorporated [3H]-thymidine at a level comparable to ConA or antigen-stimulated cells and secreted interleukin (IL)-2 at comparable levels Anti-TCR activated blasts were greater than 90% positive for CD3 and alpha/beta TCR, 60% CD4+ and 30% CD8+. PL/J or (SJL x PL)F1 recipients of anti-TCR-activated spleen cells from syngeneic normal mice also had more severe EAE than control mice following immunization with MBP. Non-responder C57BL/10SnJ mice could be converted to responders by infusion of anti-CD3 or anti-V beta 8 monoclonal antibody-treated syngeneic spleen cells taken from normal syngeneic unimmunized mice.     

In vivo and in vitro studies of the prevention of proteolipid apoprotein-induced murine experimental allergic encephalomyelitis by monoclonal antibody against L3T4

The suppressive effect of anti-L3T4 monoclonal antibody (mAb) on murine experimental allergic encephalomyelitis (EAE) induced by sensitization with proteolipid apoprotein (PLP) was examined in vivo and in vitro. This mAb inhibited the antigen-specific proliferation of the encephalitogenic T cell lines but did not block the mitogen-mediated response. Serial injections of the mAb during the pre-effector phase of EAE markedly suppressed the development and relapse of the disease but this treatment initiated after appearance of clinical signs was not effective. In treated animals, L3T4+ T cells in the spleen were profoundly decreased and the antigen-specific proliferative response of spleen cells was completely suppressed. Moreover, adoptive transfer of spleen cells from the treated mice induced resistance against EAE induction in the recipients. However, no obvious evidence for antigen-specific suppressor cells was found in vitro in the L3T4- populations of spleen cells from treated mice.     

T cell receptor Vβ gene utilization in myelin basic protein specific clones from CXJ1 recombinant inbred mice

CXJ1 mice are a recombinant inbred strain generated from experimental allergic encephalomyelitis (EAE) resistant BALB/c and EAE susceptible SJL/J progenitors. CXJ1 derive their major histocompatibility complex (MHC) class II and TCR genes from the BALB/c progenitor. However, their susceptibility to EAE is similar to SJL/J. Utilizing myelin basic protein (MBP)-specific CD4⁺ hybridoma clones and a MBP-specific T cell line (TCL) from CXJ1, we found the predominant T cell receptor (TCR) Vβ chain expression to be Vβ8 and Vβ13. Our data support the concept of preferential, but not exclusive, TCR Vβ usage in the MBP-specific response which is independent of MHC class II haplotype or immunodominant peptide.     

A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE

Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE. Starting on day -7, animals were given daily injections (s.c.) of derivatives (3.0 mg) in vehicle, or vehicle alone for 33 days. Both HE2500 and HE2200 significantly delayed the onset, reduced the peak clinical score and cumulative disease index of EAE, and prevented or significantly attenuated relapses. Lower doses or other routes of administration were less effective. Moreover, T cells from treated mice had significantly reduced PLP 139-151-specific T cell proliferation responses and reduced numbers of TNF-alpha- and IFN-gamma-producing cells in the CNS. Daily treatment of B10.PL mice with HE2500, starting on day 0, completely prevented the development of disease in these animals. Finally, SJL mice treated with HE2500 at EAE onset showed significantly reduced mean clinical scores. Thus, these compounds, which have been reported to have a few androgenic or estrogenic side effects, appear to have a potent inhibitory activity in EAE. These observations suggest that HE2500 and/or HE2200 limit the production of autoimmune Th1 associated cytokines, and ultimately may be beneficial for patients with MS or other autoimmune diseases.     

Acute experimental allergic encephalomyelitis in SJL/J mice induced by a synthetic peptide of myelin proteolipid protein

Clinical, histologic, and ultrastructural characteristics of acute experimental allergic encephalomyelitis (EAE) induced by sensitization with a synthetic peptide corresponding to mouse myelin proteolipid protein (PLP) residues 139-151 HCLGKWLGHPDKF were studied in SJL/J mice. Groups of mice were immunized with 20, 50, or 100 nmol of the peptide and were killed from seven to 28 days after sensitization or when they were moribund. Beginning on Day 9, the mice showed signs of EAE and the disease progressed rapidly to paralysis. Central nervous system (CNS) inflammation, edema, gliosis, and demyelination were found in all mice killed between Days 10 and 28 and white matter lesion areas correlated with clinical score at the time the mice were killed. Peripheral nerve roots and the cauda equina did not have lesions. Within the range studied, the severity of clinical or histologic disease was the same regardless of the PLP peptide dose. Two of ten mice immunized with 100 nmol and none of 14 mice given smaller doses of a synthetic peptide of mouse myelin basic protein (MBP) showed clinical EAE. These mice had small numbers of CNS lesions that were indistinguishable from those in PLP peptide-sensitized mice. These findings demonstrate that immunization of SJL/J mice with PLP peptide 139-151 produces a disease with the clinical and morphologic features of CNS tissue-, whole PLP-, whole MBP-, and MBP peptide-induced acute EAE. Thus, PLP is a major encephalitogen and immune reactions to epitopes of different myelin proteins may induce identical patterns of injury in the CNS.