Supplementary Table 1 Complete overview of published therapeutic approaches in
experimental autoimmune neuritis
EAN pathology
Therapeutic approach
Candidate therapeutic agent
Part 1: Antigen presentation and T-cell activation (Figure 1A)
Induction of autoreactive TCR antibody
Nonspecific anti-TCRα/β antibody1
T cells
TCR DNA vaccination
Anti-TCR Vβ4 antibody2
TCR Vβ5, TCR Vβ8.2 DNA vaccine3
Tolerance induction
– by myelin components
Nonspecific T-cell
activation
– T-cell activation
– Immune modulation
APC–T cell interaction:
interaction of the
trimolecular complex
(MHC, antigen, TCR)
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
– by ganglioside homologs
‘Complementary’ P2 peptide16
Brain gangliosides17–19
Immunosuppression
Ciclosporin A20–22
Tacrolimus (FK506)23
Ras inhibitor
Farnesylthiosulfate24
Monoamine reuptake
inhibitors
Zimeldine25,26
Clomipramine, imipramine27
TH2 shift/DMARDs
(also B-cell inhibition)
Leflunomide28
Linomide29–31
Leflunomide derivative32
Fusidin33
17β-estradiol34
Glucocorticoids
TCR antibodies
Prednisolone35–38
Nonspecific anti-TCRα/β antibody1
TCR DNA vaccination
Anti-TCR Vβ4 antibody2
TCR Vβ5, TCR Vβ8.2 DNA vaccine3
Antigen-derived therapies
(e.g. altered peptide ligands)
P2 16-polymer14
Activation of ‘second
signals’ or costimulatory
molecules
Anti-T-cell antibody
Anti-IL-2R/CD25 antibody39
Anti-pan-T-cell antibody40
Anti-CD4 antibody41
Expansion and activation of T Superagonistic anti-CD28 antibody42
regulatory cells
Part 2: B-cell activation and antibody formation (Figure 1B)
B-cell suppression
Ciclosporin A20–22
Humorally mediated
Tacrolimus23
damage
Imunoglobulins
IVIg43
Human IVIg44,45
Immunoadsorption46
Plasma exchange47
Plasma infusion48
Complement inhibitors or
depletors
Soluble complement receptor 149,50
Cobra venom factor51–53
APT07054
Part 3: Cytokine profile (Figure 1C)
Cytokine
dysregulation/Th1 shift
– Proinflammatory
Reduction of
cytokines
proinflammatory cytokines
TNFα antagonists/inhibitors
– Anti-inflammatory
cytokines
Supplementing antiinflammatory cytokines
Cell recruitment into the
PNS
Targeting immunoglobulin
superfamily adhesion
molecules (ICAM-1, VCAM)
Chemokines, cytokine
modulators,
phosphodiesterase inhibitors
Matrix metalloproteinase
inhibitors
Soluble TNF receptor 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
Targeting L-selectin
Anti-L-selectin antibody73
diapedesis
Targeting integrins (VLA4,
Anti-VLA4 antibody74
LFA1)
Anti-LFA1 antibody75
Blood–brain barrier
disruption
Anti-ICAM1-Ab76
Anti-VCAM-Ab74
Rolipram, pentoxifylline60–62
BB110163
Cytokines
Anti-cytokine antibody, cytokines (see
Part 3)
Part 5: Macrophage activation and tissue damage (Figure 1E)
Soluble toxic mediators
Cytokine modulators
Anti-cytokine monoclonal antibodies,
cytokines56–59
Cell-mediated damage
– CD4+, CD8+ T cells
– Macrophages
Humorally mediated
damage
– Antibodies
– Complement system
MMP inhibitors
BB110163
Protease inhibitors
– COX inhibitors
– COX2 inhibitors
EACA, pepstatin77
Indomethacin78
Celecoxib, meloxicam79
Nimesulide80,81
Peroxidation inhibitors
Tirizalad mesylate82
Radical scavengers
Catalase, SOD83
iNOS inhibitors
Immunosuppression
L-NMMA84
Prednisolone35–38
Ciclosporin A20–22
Tacrolimus23
Macrophage inhibitors
Silica quartz dust85,86
Cl2-MDP liposomes87
Anti-macrophage cytokines
MIF88
Anti-macrophage cytokine
antibody
Anti-MIP1 antibody, anti-MCP1
antibody89
Immunoglobulins
IVIg43
Human IVIg44,45
Immunoglobulin adsorption46
Immunoglobulins in plasma
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 blocker
Flecainide90
Complement inhibitors or
depletors
Potassium channel blocker
Quinidine91
ACTH peptide
ACTH4-992
Soluble toxic mediators
– MMPs
MMP inhibitors
BB110163
– Proteases
Protease inhibitors
EACA, pepstatin77
Arachidonic acid-derived:
– Free radicals
– COX inhibitors
– COX2 inhibitors
Indomethacin78
Celecoxib, meloxicam79
Nimesulide80,81
Myelin lipid peroxidation
Tirizalad mesylate82
Radical scavengers
Catalase, superoxide dismutase83
iNOS
L-NMMA84
Part 7: Programmed cell death and apoptosis (Figure 1G)
Auto-reactive T-cell
Tolerance induction
survival/induction of
– by myelin components
Myelin4,5
apoptosis
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
– by ganglioside homologs
Schwann cell apoptosis
Apoptosis inhibition
Part 8: Failed therapeutic studies in EAN
Tolerance induction
Brain gangliosides17–19
Anti-TNFα antibody57
Intradermal BPNM93
Antibody reduction
IVIg94
Neurotrophic axon protection
BDNF95
T-cell targeting
T-cell vaccination96
Neurotrophic cytokine
Leukemia inhibitory factor97
Anti-TCR antibody
Anti-TCR Vβ4 antibody98
Fish oil-enriched diet99
NK cells
Anti-NK-cell antibody100
Part 9: Therapeutic approaches that cause a deterioration of the EAN phenotype
Proinflammatory cytokine
IL12101
Thalidomide102
CTLA-4
Anti-CTLA-4 antibody103
CD5
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 functionassociated antigen 1; L-NMMA, L-monomethyl arginine; MCP, monocyte
chemoattractant protein; MIF, macrophage migration inhibitory factor; MIP,
macrophage inflammatory protein; NK cells, 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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