M in i Review Int Arch Allergy Immunol 1992;98:181-188

Division of Rheumatology/AIlergy and Clinical Immunology, University of California at Davis, Calif., USA; Department of Pathology, Emory University School of Medicine, Atlanta. Ga„ USA

Key Words Autoimmunity Systemic lupus erythematosus Vaccination T cell receptor Autoantibodies New Zealand mice Myasthenia gravis

Prospects of Vaccination in Autoimmune Diseases

Abstract Over the past several years, intensive efforts have been directed to define the pathogenic mechanisms and explore the potential immunotherapy of autoim­ mune diseases. The advances of molecular genetics and cellular immunology have now permitted select experimental immunotherapy using synthetic pep­ tides, T cell receptor idiotypes and monoclonal antibodies. There remain many obstacles for success. First, the T cell receptor usage of autoreactive T cells in human autoimmune diseases are more heterogeneous than animal models. Clearly, there may not be an oligoclonal derivation of T cells in humans with autoimmune diseases. We foresee that the following studies might contribute to further understand pathogenic mechanisms and design feasible immuno­ therapy: (1) detailed characterizations of self-antigen specific T cell clones; (2) definition of interactions between MHC molecules and T cell receptors at the molecular level; (3) identification and elution of relevant disease inducing self­ peptides complexed with MHC molecules and (4) identification of relevant genes that predispose to autoimmunity.

Introduction Multiple pathogenic mechanisms have been offered to explain the development of autoimmunity and the failure to maintain self-tolerance. Several well-developed experi­ mental animal models of autoimmunity have been studied [1] in efforts to gain insight into each of these potential mechanisms and to derive unique therapeutic mecha­ nisms and to derive unique therapeutic strategies. Such models include organ-specific autoimmune diseases such as myelin basic protein (MBP)-induced experimental al­ lergic encephalomyelitis (EAE, multiple sclerosis); acetyl­ choline receptor (AchR)-induced experimental autoim­ mune myasthenia gravis (EAMG, myasthenia gravis); type II collagen or proteoglycan-induced arthritis (rheu­ matoid arthritis); and thyroglobulin-induced autoimmune

thyroiditis (Hashimoto’s thyroiditis) [2-4], It should be noted that experimentally, i.e., with adjuvant, induced au­ toimmune thyroiditis is not a model for human Hashimoto thyroiditis because there are no germinal centers in the thyroid and there is absence of microsomal autoantibo­ dies; nonetheless, a great deal of data has been learned from this model as well as thyroiditis in the obese chicken. There are also several well-characterized spontaneous au­ toimmune diseases including systemic lupus erythemato­ sus (SLE) in MRL- and NZB-derived mice, and insulindependent diabetes mellitus (IDDM) in nonobese dia­ betic mice and BB/W rats [5-7]. The purpose of this review is to discuss the present knowledge of the mechanisms in­ volved in prototypes, including both human disease and spontaneous and experimentally induced animal models of autoimmune diseases in order to define the potential

Correspondence to: D r M. Eric Gershwin Division of Rheumatology/AIlergy and Clinical Immunology. University of California at Davis T B 192, School of Medicine Davis, C A 9561ft (U S A )

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Bor-Luen Chieing* Aftab Ansarib M. Eric Gershwina

IgG anti-dsDNA Ab helper activity

NZB/W FI

SNF1

NZB.H-2bml2

yes

yes

yes

|_j_9 d/z,d.z

H-2d/q CD4+ or CD4- CDS“ NA 4.6,8.1,8.2

H-2bml2 CD4+ or CD4- CD8TH-2/TH-0 4, unknown

MHC restriction Phenotype

CD4+

Lymphokine pattern V/p usage

TH-2 NA

NA. not available.

immunotherapeutic strategies that could be employed in man. Three of these diseases, EAE, EAMG and SLE will be discussed in detail to discuss the state-of-the-art poten­ tial for immunotherapy. At present, therapeutic strategies in these models are generally directed at various modalities involving general­ ized immunosuppression. Recent data, however, suggest that the development of autoimmunity is secondary to a dysfunction of the normal immune regulatory network. The goal of this paper is to discuss the pathogenic role of immune dysrégulation and to explore therapeutic strate­ gies that can be potentially directed at restoration of nor­ mal regulatory function.

The Role of T Cells in Autoimmunity T cells play an important role in the natural history of both systemic and organ-specific experimental autoim­ mune diseases. In organ-specific diseases such as EAE and EAMG, pathology can be induced with self-antigens such as the AchR or MBP. Passive transfer of AchR- or MBP-specific T cells can transfer disease [8, 9], In colla­ gen-induced arthritis, type II collagen specific cloned T cell lines are important in maintaining the persistent in­ flammation of arthritis [10]. In animal models of SLE, in­ cluding NZB-derived, MRL and BXSB mice, both in vivo and in vitro studies have suggested that T cells are critical for the production of pathogenic IgG anti-dsDNA anti­ body [11,12]. Autoreactive T cells are defined as T cells which are stimulated by self-antigens [13]. In EAE, EAMG and col­ lagen-induced arthritis, the antigens recognized by autoreactive T cells have been clearly established. However,

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the autoreactive T cells present in murine lupus have not been characterized and the immunoreactive epitopes en­ gaged by these T cells are unknown. Several studies have demonstrated that autoreactive T cells can induce B cells to differentiate into cells capable of IgG production. This T cell-dependent process is MHC-rcstrictcd whereas IgM production is not [14, 15] and involves recognition of the putative autoantigen peptide complexed with MHC mole­ cules by the appropriate T cell receptor. The genes encoding the T cell receptor are members of the immunoglobulin supergene family which include immunoglobulin, MHC, TcR, the thy-1 glycoprotein and some cell adhesion molecules [16], The TcR glycoprotein dimers expressed on the T cell surface are capable of spe­ cifically binding to peptides bound to MHC molecules. Thus far, different T cell receptor genes have been charac­ terized, and these include the a, p, y, and 8 genes. T cells express either the ap or the y8 TCR; the former T cell re­ ceptor accounts for most peripheral T cells in humans and in mice. The rearrangement of VDJ regions of the T cell receptor genes is similar to that of immunoglobulin genes. In contrast to immunoglobulin genes, no somatic muta­ tions have been recognized in T cell receptor genes [17], In mice at present, a total of 25 different Vp genes have thus far been defined. Since specific sequences of autoantigenic peptides complexed to MCH-class II molecules induce peptidespecific T cell activation in autoimmune mice, it appears reasonable to assume that such peptide-M HC class II complexes interact with specific clones of T cells express­ ing unique T cell receptors. Thus, considerable effort is being made to identify, develop and characterize TcR-expressing antigen-specific cloned T cell lines in experimen­ tal and human autoimmune diseases. A noted above, MBP- and AchR-specific cloned T cell lines have been found to transfer disease to naive animals. In addition, helper T cells specific for anti-DNA antibodies have been reported in NZB/W FI, SNF1 and NZB.H-2bml2 mice (ta­ ble 1). These autoreactive T cells can help B cells produce IgG antibodies to single stranded (ss) and double stranded (ds) DNA. Studies of SNF1 mice have demonstrated that cloned T cell lines can accelerate renal diseases in young mice [18], In addition, the 16/6 idiotype specific cloned T cell lines in­ duce disease in nonautoimmune mice [19], Although the pathogenic mechanisms are different in these two models, they collectively demonstrate that development of lupus can be induced by in vivo transfer of cloned T cell lines most likely expressing unique TCR as pertains for EAE and EAMG. Therefore, more detailed studies of auto­

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Table 1. Summary of autorcactivc T cell lines in NZB-tlcrived

mice

The Role of B Cells in Autoimmunity In murine lupus, polyclonal B cell hyperactivity is one of the notable characteristics. 13 cells are important in mu­ rine lupus due to their production of autoantibodies in­ cluding antierythrocyte antibodies, naturally occurring thymocytotoxic autoantibody and anti-ss, dsDNA anti­ bodies; the CD5+ subpopulation participates strongly in this autoantibody production [20]. It is important to note that such autoantibody production has been shown by Klinman et al. [21] to be due, not to an increase in the rela­ tive frequency of autoantibody producing B cells, but rather a generalized polyclonal activation of B cells in these autoimmune mice. Such polyclonal activation might break the threshold of maintaining normal immune re­ sponses. In other words, these self-antigen-specific B cells might be relevant to diseases by being more efficient in presenting the epitopes of self-antigens to autoreactive T cells, thus influencing the subsequent development of au­ toimmune responses. Some autoreactive T cells respond to unstimulatcd B cells but not lipopolysaccharide-activated B cells, suggest­ ing that peptides complexed with MHC molecules prob­ ably are different in these two sets of antigen-presenting cells [22], These results imply the possible presence of self­ antigen complexed with MHC molecules in resting B cells which are capable of activation of autoreactive T cells. Several studies have also suggested that processed pep­ tides can be precipitated and isolated from MHC mole­ cules using anti-MHC antibody-conjugated columns [23], Recently, Rudensky et al. [24] isolated processed peptides complexed with MHC class II molecules and demon­ strated that most were endogenous in origin. It is possible that some self-antigens might be processed and presented with MHC molecules persistently in vivo. In normal ani­ mals, the self-antigen-MHC complex could be important in maintaining self-tolerance [25]. However, a dysfunction of normal immune regulation might result in expansion of the autoreactive B cells which process and present self­ antigens to autoreactive T cells [26], Subsequent abnormal expansion of autoreactive T cells would then result in a failure to maintain self-tolerance. Recently, Erikson et al. [27] reported anergy of a DNA-binding B cell population in anti-DNA antibody Vh gene transgenic mice.

Adams et al. [18] also suggest that anti-dsDNA antibod­ ies augment T cells by cationic self-peptides presented by anti-DNA antibody-producing B cells. These findings might explain the role of an abnormal expanding B cell population in murine lupus. Again, if this is true, blocking the interaction between an MHC-self-antigcn complex and T cell receptors will have potential for treatment. It will also be interesting to determine if B cell populations do in fact present self-antigens to T cells in autoimmuneprone mice. EA E is recognized to be a cell-mediated disease and no role for B cells has been established. In contrast, AchRspecific antibodies are thought to be responsible for dis­ ease pathogenesis in EAMG as for the disease in man. Re­ cently, the B cells identified in the thymus of patients with myasthenia gravis have been found to be activated and produce anti-AchR antibodies in vitro without stimulation in vitro [28]. These data suggest that autoreactive B cells in MG patients might recognize AchR antigens presumably expressed on epithelial cells in the thymus and indicate a breakdown in self-tolerance. It is a reasonable hypothesis that autoreactive B cells expand spontaneously, and that appropriate immunization with self-antigens will break the threshold for maintaining self-tolerance.

The Role of APC and MHC Molecules Aberrant expression of class II MHC molecules on pa­ renchymal cells of the target organ in organ-specific au­ toimmune diseases has been reported in human thyroid­ itis and IDDM and in model diseases including EAE [29]. Further, disease development in EAE, EAMG and mu­ rine lupus has been associated with certain MHC haplotypes. EAE can be induced in mice carrying H-2S (SJL) and H-2U(B10.PL) haplotypes. In EAMG, disease can be induced by immunization with AchR in C57BL/6 but not B6.C-H-2bm12 mice [30], Further studies have demon­ strated that T cells in B6.C-H-2bml2 mice do not respond to epitopes defined by T cell clones derived in B6 mice [31,32], Essentially, these data suggest that T cell recognition re­ quires that particular autoantigens can only be processed and complexed with particular MHC molecules. This find­ ing might also partly explain the genetic contribution of the MHC complex to the pathogenesis of autoimmunity. In­ terestingly, an influence of the bml2 mutation has been found on the production of anti-DNA antibodies [33], Gene products of the MHC have been shown to be a key factor in IgG anti-dsDNA antibody production [34]. In contrast to congcnic NZB.H-2b mice, NZB.H-2bm12 mice

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reactive T cells, including sequence analysis of TcR genes, determination of epitopes engaged by the TcR, and inter­ action with antigen presenting cells, should provide con­ siderable insight.

EAE SJDJ(H-2S) PL/J(H-2U) B10.PL(H-2U) Lewis rat Rabbit EAMG Lewis rat C57BL/6 SLE NZB/W FI SNF1 NZB.H-2broi: MRL.lpr/lpr

Epitopes

Receptor genes

MBP MBP MBP MBP MBP

V|H7a V|}8.2, 4; V«4 V|58.2, 13; V«2,4 V|)8.2; Va2

89-169 1-37 1-37 1-9 15-31

vps

AchR a subunit 73-90; 100-116 AchR « subunit 148-152

? ?

unknown unknown unknown unknown

NA V|14.6,8.1, 8.2 V[14 NA

develop IgG anti-dsDNA antibodies and glomerulone­ phritis [33], The bml2 mutation is the only defined class II mutation involving residues 67, 70 and 71 of I-Apb mole­ cules; this corresponds to amino acids 68,71 and 72 of I-E[I chain because of a splicing difference [35]. Position 67-71 of the I-A molecule is located inside to a-helix which is thought to play an important role in antigen binding and recognition [36]. T cell recognition of a number of other antigens is also affected by these three mutated amino acids, i.e. beef insulin, H-Y antigen and the AchR immune response [31, 37].

Epitopes and Idiotypes In EAE and EAMG, the self-antigens necessary to in­ duce disease are well-defined, and MBP- and AchR-specific cloned T cell lines have been established. The epi­ topes engaged by T cells, and T cell receptor usages in EAE, EAMG and murine lupus are summarized in table 2. The epitopes engaged by helper T cells are distinct in mice with different MHC haplotypes, and distinct again for dif­ ferent species. For example, amino acids 1-37 of MBP are recognized by H-2Uand 89-169 by H-2Smice [38]. In the rat, amino acids 1-9 in H-2Uand 87-98 and 91-104 in H-2Shave been defined [39,40], In EAMG, the major epitopes for T cell recognition are found in the a subunit of AchR. In con­ trast, the antigenic determinants for both B cells and T cells in SLE arc still not known; however, nucleohistoncs released in vitro can stimulate proliferation of lympho­ cytes [41]. Recently, Adams et al. [18] have suggested that

184

the possible antigenic determinants for the autoreactive T cells are cationic nucleoproteins conjugated with DNA. With the derivation of T helper cells that induce anti-DNA antibody definitive information on the antigenic determi­ nants can be expected in the next several years. In SLE and EAMG the idiotypes of autoantibodies have been well studied. In murine lupus, Id GN1 and Id GN2 have been re­ ported to be pathogenic in NZB/W FI mice [42], The possible contribution of the idiotype network in the pathogenesis of EAMG has been described [43, 44]. The isolation of autoantigen-specific cloned T cell lines has facilitated the delineation of the T cell receptor gene. In EAE, preferential V[18 usage has been noted in mice, rats and rabbits. The susceptibility and resistance of colla­ gen-induced arthritis was found to be related to Vp6-T cell receptor genes [45, 46], In Lewis rats and rabbits the se­ quences of the MBP-spccific cloned T cell lines corre­ spond to Vp8-J(I2 genes in the mice. In contrast, the Vpi7a TcR gene product was noted in about 50% of the encephalitogenic cloned T cell lines from SJL mice [47,48], In ad­ dition, in Vpi7a" SJL/J mice Vp4-bearing encephalitogenic cloned T cell lines were derived [49], The V|34-TcRbearing T cell lines specific for MBP have also been found in (PL x SJL) FI mice. These data generally support the V-region hypothesis [50] which specifies a similar TcR gene usage for responses to MBP even across species. In SNF1, Vp TcR analysis of autoreactive T cell lines showed that the Vp4, 6 and 8.1, 8.2 TcR were used among the T cell lines identified [51]. In contrast to SNF1 mice, the V[] TcR 4, 6 bearing cloned T cell lines were shown to induce anti-DNA antibodies in NZB.H-2bm12 mice. In SNF1 mice, CD4~/CD8~ the so-called double negative au­ toreactive T cell lines expressing Vp6 and 8.1 have been re­ ported. However, mature T cells expressing Vp6 and Vp8.1 should be deleted in IE + mice bearing Mlsa determinants [52, 53], In NZB.H-2bml2 mice, one double negative T cell clone has also been noted. In the human, the data thus far appears similar to that observed in animal models. Some TcR gene usage studies have suggested a degree of oligoclonality of T cells by re­ striction fragment length polymorphism for T cells from cerebrospinal fluid of patients with multiple sclerosis, and joint fluid from patients with rheumatoid arthritis [54-58]. Recently, Oksenbcrg et al. [58] used PCR to study T cell V a transcripts and suggested a limited heterogeneity among the T cells found in brains of multiple sclerosis pa­ tients. These initial findings are highly significant if one considers the heterogeneity of the MHC in humans as compared to that of animals. The effects of a different MHC might contribute to the diverse immune responses

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Table 2. T cell epitopes and T cell receptor genes in animal models of autoimmune diseases

Table 3. Disadvantages of immunotherapy

Therapies

Models

Disadvantages

Immunosuppressive Immune modulators Diet therapy TNF-a Anti-INF-a and anti-IL2R Anti-id Ab or Ts cells Anti-CD4 ot T cell markers Ab Anti-V|t Ab mAh specific for T cell receptors Inactivated T cells vaccination Synthetic peptides vaccination Anti-la Ab Anti-la Ag complex Ab Blocking peptides

SLE. EAE SLE, EAE SLE SLE SLE SLE SLE; EAE; EAMG EAE EAE EAE; EAMG EAE SLE; EAE; EAMG EAE EAE

Suppress normal regulatory responses at the same time Unknown mechanisms Unknown mechanisms Side effect Side effect Inconsistent; possible idioptype ‘switch’ Nonspecific Elimination of single V|} might not be enough

Therapy of Autoimmune Disease Conventional therapy for both organ-specific or sys­ temic diseases is generally based upon immunosuppres­ sive therapy. In contrast, the concept of immunotherapy has arisen from the anti-idiotypic network and inhibition of self-antigen presentation. Several possible approaches arc summarized in table 3. Immune modulators including cyclosporin A, thymopentin and neurotropin have been used to treat EAE and murine lupus with some success

Inconsistent; not effective for EAMG MHC-related nonresponders? Nonspecific

?

Nonspecific; high cost; short life span

[62,63]. Although the mechanisms of these immune mod­ ulators are still not known, they might restore regulatory T cells. Induction of specific cytokines such as TNF-a in mu­ rine lupus has been found to have a beneficial effect on dis­ ease [64], In murine lupus, interferon-y has been shown to aggravate disease, perhaps by up-regulating the expression of MHC class II moleculeson the surface of APC with a sub­ sequent abnormal expansion of autoreactive B and T cells. Further study has shown that anti-IFN-y antibodies can re­ verse the disease process caused by IFN-y [66]. Studies with anti-IL2 receptor monoclonal antibodies also showed sup­ pressive effects on IDDM and murine lupus [66]. The use of anti-idiotypic antibodies directed toward autoantibodies has been tried in murine lupus [67-69], The effects of anti-id antibodies are often transient; large quantities of different id-bearing anti-DNA antibodies ap­ pear following treatment. Recently, anti-idiotypic anti­ bodies conjugated with cytotoxic agents have been used to treat murine lupus with some encouraging results. None­ theless the potential use of idiotypes to modulate disease is still very unclear and requires further study [71]. In the future, a mixture of anti-idiotypic antibodies might be used to prevent idiotype switch during treatment. Idiotype-specific suppressor T cells directed toward the 16/6 idiotype have been developed by priming the T cells with idiotype coated on silica beads in vitro [70], These regu­ latory cells can decrease the proliferation of idiotype-specific T helper cells and delay disease activity. Based upon the in vivo role of T cell clones, experi­ mental protocols designed to modulate and/or eliminate autoreactive T cells have been tried. In limited studies, some success has been achieved by in vivo treatment with anti-L3T4, anti-la antibodies or anti-Vp antibodies [72],

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even to the same antigens. In infectious diseases, different HLA types have been thought to confer unresponsivencss during vaccination [59]. There are more different Va and VP T cell receptor genes in humans than in mice. It is thus unknown if the V-region hypothesis can be strictly applied in heterogeneous populations of humans with autoim­ mune diseases. More data about T cell receptor usage in human autoimmune diseases is therefore needed to re­ solve this issue. Idiotypic network regarding B cells has been noted in murine lupus. Puccetti et al. [60] used a shared sequence in the ribonucleoprotein antigen and immunoglobulin light chain of an autoantibody to successfully induce the pro­ duction of autoantibodies in normal mice. Other data sug­ gesting that the idiotypic network is important to the pathogenesis of lupus in mice is the observation that the human anti-DNA antibodies bearing the 16/6 idiotype in­ duce lupus in nonautoimmune mice [61]. The 16/6 idiotype specific T cells have also been demonstrated to cause lupus in mice [19], In EAMG, a cross-reactive idiotype has also been reported among the AchR-spccific autoantibodies.

?

186

The number of attenuated T cells used for vaccination is also critical for protection [91] and there is still contro­ versy regarding the effective dose; the dose of vaccine might depend on the immunogenicity of the cloned T cell lines. More recently, peptides from T cell receptor varia­ ble regions have been used as vaccines to treat EAE with some success [74, 92]. Irradiated or mitomycin-treated cloned T cell lines have been used to immunize naive ani­ mals and prevent disease induction either by MBP or by passive transfer of MBP-specific T cells. In the B10.PL mouse and Lewis rat, sequence analysis of T cell receptor specific for MBP suggests very limited usage of both V|3 and V a genes [47], Some success has been achieved to pre­ vent disease development by vaccination of synthetic pep­ tides from T cell receptors. Howell et al. [74] used syn­ thetic peptides corresponding to idiotypic determinants of [3 chain VDJ regions and Ja regions to immunize rats. In contrast, synthetic peptides derived from second comple­ mentarity determining region (CDR2) of V(3 T cell recep­ tors also can prevent disease development in rats [92]. The experimental treatments directed toward EAMG and mu­ rine lupus have not been well documented. The use of in­ activated T cell vaccine in EAMG is not very successful, probably due to the relatively heterogeneous usage of the T cell receptor genes. Treatment with anti-la antibodies has been shown to have a potent effect on the natural history of EAE, EAMG and murine lupus [93]. Recently, monoclonal antibodies directed toward the Ia-Ag complex has been used to treat EAE [94]. This approach is both self-antigen- and haplotype-specific compared to anti-la antibodies. In vivo de­ pletion of macrophages by silica dust or mannosylated li­ posome containing dichloromethylene diphosphate (C12MDP) has been shown to have a beneficial effect on EAE [95, 96]. Another possible therapeutic application is to use syn­ thetic peptide analogs to compete with T cell epitopes of self-antigens at the MHC and T cells receptor interaction level. Since T cell-MHC interaction is critical to the devel­ opment of autoimmune diseases, efforts have been made to use peptide analogs to bind to the MHC molecules without stimulating T helper cells [97, 98]. However, the disadvantages of this approach include nonspecificity and a short life span which might limit clinical application (table 3).

Acknowledgements Supported by NIH grant CA 20816. The authors appreciate the editorial comments of Dr. Ian Mackay.

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Moreover, inactivated cloned T cell lines have been used as vaccines to treat EAE, EAMG and autoimmune thy­ roiditis [73]. However, the efficiency of inactivated or at­ tenuated T cell vaccines is not very consistent. Synthetic peptides derived from self-antigen-specific T cell recep­ tors have also been used to immunize and prevent disease induction [74], Treatment with anti-CD4 has been shown to alleviate and delay the onset of disease in several animal models in­ cluding murine lupus, EAE and EAMG [11, 75-78], AntiCD4 antibodies have been shown to prevent disease in­ duction by MBP in naive mice and to reverse paralysis in diseased animals [77, 78], In addition, monoclonal anti­ bodies directed against T cell markers also can prevent the development of EAE in vivo [79]. In B10.PL mice and Lewis rats the V|38-bearing TcR are found to be prefer­ entially used by the MBP-specific T cells. Anti-V(38 anti­ bodies have been administered to treat EAE in these ani­ mals with partial success [82], Obviously, antibody to a specific subset of T cells is preferable to anti-CD4 anti­ body treatment. The success of anti-Vfl antibody treat­ ment supports the V-region hypothesis. Thus, autoreactive T cells possessing dominant V[3 receptors and conser­ vative VDJ region might be eliminated even more specifically by using anti-idiotypic antibodies or by vacci­ nation [80]. Anti-T cell receptor idiotypic antibodies have been demonstrated to have regulatory effect on T helper cells [81]. In both Lewis rats and rabbits, antibodies against the TCR-V|38 which specifically recognize the 39-59 pep­ tide were found to be tolerogenic [82], Oral tolerization of self-antigens also has been applied to EAE treatments. Immunization of animals with inactivated or atten­ uated self-antigen-specific T cell lines or clones could re­ sult in down-regulation of autoreactivc T cells by the mechanisms of anti-idiotypic antibodies or idiotype-specific regulatory T cells [83, 84], Inactivated or attenuated lymphocytes or T cells have been used as vaccines to treat experimental autoimmune diseases including EAE, adju­ vant arthritis and autoimmune thyroiditis [85-92], There are several methods used to inactivate T cells, i.e. irradia­ tion, mitomycin c, hydrostatic pressure or ganglioside treatm ent [85]. Irradiated or mitomycin-treated MBPspecific T cell lines were used to immunize naive animals and prevent the symptoms of EAE in animals challenged with MBP [85]. Further studies demonstrated that T cell lines treated with hydrostatic pressure or with a chemical cross-linker like ganglioside could be a more effective vac­ cine [87]. In addition, treating T cell clones with both irra­ diation and hydrostatic pressure may increase vaccine suc­ cess [90].

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