Article

Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models

INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Hôpital Purpan, Toulouse, F-31300, France
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2011; 1812(2):151-61. DOI: 10.1016/j.bbadis.2010.07.006
Source: PubMed

ABSTRACT

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by multi-focal demyelination, axonal loss, and immune cell infiltration. Numerous immune mediators are detected within MS lesions, including CD4(+) and CD8(+) T lymphocytes suggesting that they participate in the related pathogenesis. Although CD4(+) T lymphocytes are traditionally considered the main actors in MS immunopathology, multiple lines of evidence suggest that CD8(+) T lymphocytes are also implicated in the pathogenesis. In this review, we outline the recent literature pertaining to the potential roles of CD8(+) T lymphocytes both in MS and its animal models. The CD8(+) T lymphocytes detected in MS lesions demonstrate characteristics of activated and clonally expanded cells supporting the notion that these cells actively contribute to the observed injury. Moreover, several experimental in vivo models mediated by CD8(+) T lymphocytes recapitulate important features of the human disease. Whether the CD8(+) T cells can induce or aggravate tissue destruction in the CNS needs to be fully explored. Strengthening our understanding of the pathogenic potential of CD8(+) T cells in MS should provide promising new avenues for the treatment of this disabling inflammatory disease.

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Available from: Lennart T Mars, Apr 09, 2015
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    • "The presence of CD4 + T cells and an abundance of CD8 + T cells in MS lesions is well documented [24, 25]. The efficacy of IFN beta-1a given subcutaneously three times a week (IFN β-1a SC tiw) for the treatment of RRMS has been established25262728. However, its effect on early changes in brain volume and its relationship to changes in inflammatory markers have not been investigated previously. "
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    ABSTRACT: Background Brain volume atrophy is observed in relapsing–remitting multiple sclerosis (RRMS). Methods Brain volume changes were evaluated in 23 patients with RRMS treated with interferon β-1a 44 μg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed. Results Interferon β-1a 44 μg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; –0.95 %; P = 0.030, –1.52 %; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume. Conclusions These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon β-1a 44 μg SC tiw, rather than disease-related tissue loss. Trial registration ClinicalTrials.gov; NCT01085318
    Full-text · Article · Nov 2015 · BMC Neurology
    • "Indeed, active immunization with myelin or immunodominant myelin peptides emulsified in complete Freund's adjuvant can trigger the development of EAE in various animal species (Rivers et al. 1933; Kabat et al. 1951; Stromnes and Goverman 2006b). Similarly, the adoptive transfer via peripheral routes (intraperitoneal or intravenous) of activated myelin specific CD4 or CD8 T lymphocytes is sufficient to induce EAE in naïve recipients (Stromnes and Goverman 2006a; Fletcher et al. 2010; Mars et al. 2011). Furthermore, activation of T lymphocytes recognizing myelin epitopes that are distinct from the first targeted antigen, a phenomenon coined as epitope spreading, has been shown to trigger EAE relapses (McRae et al. 1995; McMahon et al. 2005; Baxter 2007). "
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    ABSTRACT: Multiple sclerosis (MS) is the prototypic inflammatory disease of the central nervous system (CNS) characterized by multifocal areas of demyelination, axonal damage, activation of glial cells, and immune cell infiltration. Despite intensive years of research, the etiology of this neurological disorder remains elusive. Nevertheless, the abundance of immune cells such as T lymphocytes and their products in CNS lesions of MS patients supports the notion that MS is an immune-mediated disorder. An important body of evidence gathered from MS animal models such as experimental autoimmune encephalomyelitis (EAE), points to the central contribution of CD4 T lymphocytes in disease pathogenesis. Both Th1 (producing interferon-γ) and Th17 (producing interleukin 17) CD4 T lymphocytes targeting CNS self-antigens have been implicated in MS and EAE pathobiology. Moreover, several publications suggest that CD8 T lymphocytes also participate in the development of MS lesions. The migration of activated T lymphocytes from the periphery into the CNS has been identified as a crucial step in the formation of MS lesions. Several factors promote such T cell extravasation including: molecules (e.g., cell adhesion molecules) implicated in the T cell-blood brain barrier interaction, and chemokines produced by neural cells. Finally, once in the CNS, T lymphocytes need to be reactivated by local antigen presenting cells prior to enter the parenchyma where they can initiate damage. Further investigations will be necessary to elucidate the impact of environmental factors (e.g., gut microbiota) and CNS intrinsic properties (e.g., microglial activation) on this inflammatory neurological disease.
    No preview · Article · May 2015 · Journal of Neuroimmune Pharmacology
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    • "The animal model that is considered to most closely model multiple sclerosis is termed experimental autoimmune encephalomyelitis (EAE)25262728. EAE is thought to, in some aspects, replicate MS in terms of the inflammation and ensuing CNS demyelination2930. This animal model is induced by delivering an antigenic myelin-derived peptide along with an adjuvant that together initiate an inflammatory response producing autoreactive lymphocytes that target the host's endogenous myelin31. "
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    ABSTRACT: Fingolimod (FTY720) is an oral therapy for relapsing remitting multiple sclerosis (MS) and targets sphingosine 1-phosphate receptors (S1PRs). FTY720 also rescues animals from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effects of FTY720 in EAE are primarily scored manually by examining weight loss and limb paralysis that begins around 10-12 days after immunisation. To our knowledge, pre-clinical effects of FTY720 on animal behaviour early in EAE have not been explored. Here, we developed an automated behaviour monitoring system to examine the early effects of FTY720 on subtle pre-symptomatic behaviour of mice induced with EAE. Our automated home-cage monitoring system (AHC-MS) enabled non-contact detection of movement and ultrasonic vocalisations (USVs) of mice induced with EAE, thus allowing detection of subtle changes in mouse behaviour before paralysis occurs. Mice receiving FTY720 emit longer USVs and display higher levels of motor activity than vehicle-treated EAE mice before clinical symptoms become apparent. Importantly, this study promotes the 3Rs ethics (replacement, reduction and refinement) in the EAE animal model and may also improve pre-screening of potentially novel MS therapies. In addition, this is the first report showing the early effects of FTY720 in EAE which underscores its protective effects.
    Full-text · Article · May 2014 · Scientific Reports
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