Supplementary Table 1Complete overview of published therapeutic approaches in experimental autoimmune neuritis
EAN pathology / Therapeutic approach / Candidate therapeutic agentPart 1: Antigen presentation and T-cell activation (Figure 1A)
Induction of autoreactive T cells / TCR antibody
TCR DNA vaccination
Tolerance induction
– by myelin components
– by ganglioside homologs / Nonspecific anti-TCRα/β antibody1
Anti-TCRVβ4 antibody2
TCR Vβ5, TCR Vβ8.2 DNA vaccine3
Myelin4,5
Myelin + cholera toxin6
P0 peptides (aa180–199, aa56–71)7
P2 peptide (aa57–81, aa62–69)8,9
P2 protein10,11
P2 protein + prednisolone12
ADAM8 + polyepitope vaccine13
P2 16-polymer14
P2 peptide (aa53–78)-coupled splenocytes15
‘Complementary’ P2 peptide16
Brain gangliosides17–19
Nonspecific T-cell activation
– T-cell activation
– Immune modulation / Immunosuppression
Ras inhibitor
Monoamine reuptake inhibitors
TH2 shift/DMARDs
(also B-cell inhibition)
Glucocorticoids / Ciclosporin A20–22
Tacrolimus (FK506)23
Farnesylthiosulfate24
Zimeldine25,26
Clomipramine,imipramine27
Leflunomide28
Linomide29–31
Leflunomide derivative32
Fusidin33
17β-estradiol34
Prednisolone35–38
APC–T cell interaction: interaction of the trimolecular complex (MHC, antigen, TCR) / TCR antibodies
TCR DNA vaccination
Antigen-derived therapies(e.g. altered peptide ligands) / Nonspecific anti-TCRα/β antibody1
Anti-TCRVβ4 antibody2
TCR Vβ5, TCR Vβ8.2 DNA vaccine3
P2 16-polymer14
Activation of ‘second signals’ or costimulatory molecules / Anti-T-cell antibody
Expansion and activation of T regulatory cells / Anti-IL-2R/CD25 antibody39
Anti-pan-T-cell antibody40
Anti-CD4 antibody41
Superagonistic anti-CD28 antibody42
Part 2: B-cell activation and antibody formation (Figure 1B)
Humorally mediated damage / B-cell suppression
Imunoglobulins
Complement inhibitors or depletors / Ciclosporin A20–22
Tacrolimus23
IVIg43
Human IVIg44,45
Immunoadsorption46
Plasma exchange47
Plasma infusion48
Soluble complement receptor 149,50
Cobra venom factor51–53
APT07054
Part 3: Cytokine profile (Figure 1C)
Cytokine dysregulation/Th1 shift
– Proinflammatory cytokines
– Anti-inflammatory cytokines / Reduction of
proinflammatorycytokines
TNFα antagonists/inhibitors
Supplementing anti-inflammatorycytokines / Soluble TNFreceptor 155
Anti-TNFα antibody56,57
Anti-IFNγ antibody58
Anti-IL-18 antibody59
Rolipram (pde4 inhibitor)60,61
Pentoxifyllin (pde inhibitor)62
BB110163
IL-464
Ex vivo IL-4 stimulation65
IL-1066
IFNα/IFNβ67
IFNβ68
TGFβ1/TGF2β69,70
IL-17 (chronic EAN)71
IL-672
Part 4:Chemotaxis, adhesion and migration into the PNS (Figure 1D)
Adherence and diapedesis / Targeting L-selectin
Targeting integrins (VLA4, LFA1)
Targeting immunoglobulinsuperfamily adhesionmolecules (ICAM-1, VCAM) / Anti-L-selectin antibody73
Anti-VLA4 antibody74
Anti-LFA1 antibody75
Anti-ICAM1-Ab76
Anti-VCAM-Ab74
Cell recruitment into the PNS / Chemokines, cytokine modulators, phosphodiesterase inhibitors / Rolipram, pentoxifylline60–62
Blood–brain barrier disruption / Matrix metalloproteinase inhibitors
Cytokines / BB110163
Anti-cytokine antibody, cytokines (see Part 3)
Part 5: Macrophage activation and tissue damage (Figure 1E)
Soluble toxic mediators / Cytokine modulators
MMP inhibitors
Protease inhibitors
– COX inhibitors
– COX2 inhibitors
Peroxidation inhibitors
Radical scavengers
iNOS inhibitors / Anti-cytokine monoclonal antibodies, cytokines56–59
BB110163
EACA, pepstatin77
Indomethacin78
Celecoxib, meloxicam79
Nimesulide80,81
Tirizalad mesylate82
Catalase, SOD83
L-NMMA84
Cell-mediated damage
– CD4+, CD8+ T cells
– Macrophages / Immunosuppression
Macrophage inhibitors
Anti-macrophage cytokines
Anti-macrophage cytokine antibody / Prednisolone35–38
Ciclosporin A20–22
Tacrolimus23
Silica quartz dust85,86
Cl2-MDP liposomes87
MIF88
Anti-MIP1 antibody, anti-MCP1 antibody89
Humorally mediated damage
– Antibodies
– Complement system / Immunoglobulins
Immunoglobulins in plasma
Complement inhibitors or depletors / IVIg43
Human IVIg44,45
Immunoglobulin adsorption46
Plasma exchange47
Plasma infusion48
Soluble complement receptor 149,50
Cobra venom factor51–53
APT07054
Part 6:Axonal degeneration and loss of trophic support (Figure 1F)
Axonal degeneration / Sodium channel blockerPotassium channel blocker
ACTH peptide / Flecainide90
Quinidine91
ACTH4-992
Soluble toxic mediators
– MMPs
– Proteases
– Free radicals / MMP inhibitors
Protease inhibitors
Arachidonic acid-derived:
– COX inhibitors
– COX2 inhibitors
Myelin lipid peroxidation
Radical scavengers
iNOS / BB110163
EACA, pepstatin77
Indomethacin78
Celecoxib, meloxicam79
Nimesulide80,81
Tirizalad mesylate82
Catalase, superoxide dismutase83
L-NMMA84
Part 7:Programmed cell death and apoptosis (Figure 1G)
Auto-reactive T-cell survival/induction of apoptosisSchwann cell apoptosis / Tolerance induction
– by myelincomponents
– by gangliosidehomologs
Apoptosis inhibition / Myelin4,5
Myelin + cholera toxin6
P0 peptides (aa180–199, aa56–71)7
P2 peptide (aa57–81, aa62–69)8,9
P2 protein10,11
P2 protein + prednisolone12,13
ADAM8 + polyepitope vaccine13
P2 16-polymer14
‘Complementary’ P2 peptide16
Brain gangliosides17–19
Anti-TNFα antibody57
Part 8: Failed therapeutic studies in EAN
Tolerance induction
Antibody reduction
Neurotrophic axon protection
T-cell targeting
Neurotrophic cytokine
Anti-TCR antibody
NKcells / Intradermal BPNM93
IVIg94
BDNF95
T-cell vaccination96
Leukemia inhibitory factor97
Anti-TCR Vβ4 antibody98
Fish oil-enriched diet99
Anti-NK-cell antibody100
Part 9: Therapeutic approaches that cause a deterioration of the EAN phenotype
Proinflammatory cytokine
CTLA-4
CD5 / IL12101
Thalidomide102
Anti-CTLA-4 antibody103
Anti-CD5 antibody104
Abbreviations: ACTH, adrenocorticotropic hormone; TCR, T-cell receptor; aa, amino acids; BDNF, brain-derived neurotrophic factor; Cl2-MDP, dichlormethylene diphosphonate; CTLA, cytotoxic T-lymphocyte-associated antigen;DMARDS, disease-modifying anti-rheumatic drugs;EACA, epsilon amino caproic acid; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IVIg, intravenous immunoglobulin; LFA1, lymphocyte function-associated antigen 1; L-NMMA, L-monomethyl arginine; MCP, monocyte chemoattractant protein;MIF, macrophage migration inhibitory factor; MIP, macrophage inflammatory protein; NKcells, natural killer cells; P0, myelin protein zero; P2, myelin protein P2; TCR, T-cell receptor; TGF, transforming growth factor; TNF, tumor necrosis factor; VCAM, vascular cellular adhesion molecule; VLA4, very late antigen 4.
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