Animal models of multiple sclerosis--potentials and limitations

Abstract

Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-α, interferon-γ and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-β and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4+ Th1, Th2, Th3 and Th17 cells, CD4+FoxP3+ Treg cells, CD8+ Tc1 and Tc2, B cells and γδ+ T cells have been disclosed in more detail. The new insights may help to identify novel targets for the treatment of MS. However, translation of the experimental results into the clinical practice requires prudence and great caution.

Fig. 1

Timeline of milestones in the history of animal models of MS. Abbreviations: AT-EAE, adoptive transfer EAE; CD, cluster of differentiation; CNS, central nervous system; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; TCR, T cell receptor; Genain et al., 1995, Huseby et al., 2001 T helper cell.

Fig. 2

Putative auto-antigens in EAE with indication of their preferential localisation. Insets refer to the ODC membrane (inset 1), myelin surface zone (inset 2), compact myelin zone (inset 3), myelin/axon interface zone (inset 4), and nodal and paranodal zone of node of Ranvier (inset 5). Abbreviations: CNP, 2′,3′-cyclic nucleotide-3′-phosphodiesterase; cyt, cytoplasm; ext, extracellular space; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; NF, neurofascin; PLP, proteolipid protein; TAG, transient axonal glycoprotein.

Fig. 3

Most common animal models of MS with indication of the compartments investigated for analysis of systemic and local disease processes. For active immunization antigens are preferentially applied to the flank or toe pad of the animal, since draining lymph nodes of these areas mediate a highly effective systemic immune response to the putative auto-antigens as a first step for induction of autoimmune processes in the CNS. Abbreviations: AT-EAE, adoptive transfer EAE; CFA, complete Freund's adjuvant; i.p., intraperitoneal; i.v., intravenous; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; PB, peripheral blood; PLP, proteolipid protein; s.c., subcutaneous; SP, spleen, Th1 cells, T helper type 1 cells.

Fig. 4

Putative pathogenic mechanisms of MS. Auto-reactive lymphocytes may be recruited from peripheral lymphoid organs and after migration through the BBB reactivated in the CNS, where an inflammatory cascade is initiated leading to subsequent damage of myelin and axons. Alternatively, primary oligodendroglial and axonal degeneration may be followed by an inflammatory autoimmune process. The adjacent table depicts the putative pathogenic processes that are targeted by established and experimental therapies. Treatments are grouped according to the contribution made by EAE to their development, i.e. they are either successfully translated into the clinic (green), only successful in EAE (red) or currently tested in EAE and/or MS (yellow). Abbreviations: AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; APC, antigen-presenting cell; APL, altered peptide ligand; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; CD, cluster of differentiation; CNS, central nervous system; CNTF, ciliary neurotrophic factor; CRYAB, αB-crystallin; CYLA, Calpain inhibitor; 3,4-DAA, N-(3,4,-dimethoxycinnamoyl) anthranilic acid; DRD1, dopamine receptor type 1; EGCG, (−)-epigallocatechin-3-gallate; IL, interleukin; IFN-γ, interferon-γ; major histocompatibility complex; MOG, myelin oligodendrocyte glycoprotein; MP, methylprednisolone; MRI, magnetic resonance imaging; NK, natural killer; ODC; oligodendrocyte; PLP, proteolipid protein; PPAR-α, peroxisome proliferator-activated receptor-α; SSRI, selective serotonin reuptake inhibitor; Tc, cytotoxic T cell; TCR, T cell receptor; TGF-β, transforming growth factor-β; Th cell, helper T cell; TNF-α, tumor necrosis factor-α.

Fig. 5

Timeline of the pathophysiological and clinical course of EAE and MS. In EAE, the complete pathological course including the pre-clinical phase is detected and immune therapeutic interventions start early and decrease usually with the proceeding time. In MS, there is an opposite situation. First radiological signs remain usually undetected and immunomodulatory treatment starts only with first clinical signs and is usually intensified until late progression of the disease. Abbreviations: CIS, clinical isolated syndrome; CNS, central nervous system; RIS, radiologic isolated syndrome; RRMS, relapsing–remitting MS; SPMS, secondary progressive MS.