@article{4734900db08a4563afb620bbcf750695,
title = "Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis",
abstract = "Multiple Sclerosis (MS) is an immune-mediated neurological disorder, characterized by central nervous system (CNS) inflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Although autoimmunity, inflammatory demyelination and neurodegeneration underlie MS, the initiating event has yet to be clarified. Effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. The challenge in developing an effective long-lived therapy for MS requires that three disease-associated targets be addressed: (1) self-tolerance must be re-established to specifically inhibit the underlying myelin-directed autoimmune pathogenic mechanisms; (2) neurons must be protected from inflammatory injury and degeneration; (3) myelin repair must be engendered by stimulating oligodendrocyte progenitors to remyelinate CNS neuronal axons. The combined use of chronic and relapsing remitting experimental autoimmune encephalomyelitis (C-EAE, R-EAE) (“outside-in”) as well as progressive diphtheria toxin A chain (DTA) and cuprizone autoimmune encephalitis (CAE) (“inside-out”) mouse models allow for the investigation and specific targeting of all three of these MS-associated disease parameters. The “outside-in” EAE models initiated by myelin-specific autoreactive CD4+ T cells allow for the evaluation of both myelin-specific tolerance in the absence or presence of neuroprotective and/or remyelinating agents. The “inside-out” mouse models of secondary inflammatory demyelination are triggered by toxin-induced oligodendrocyte loss or subtle myelin damage, which allows evaluation of novel therapeutics that could promote remyelination and neuroprotection in the CNS. Overall, utilizing these complementary pre-clinical MS models will open new avenues for developing therapeutic interventions, tackling MS from the “outside-in” and/or “inside-out”.",
keywords = "animal models, autoimmunity, demyelination, etiopathogenesis, multiple sclerosis",
author = "Titus, {Haley E.} and Yanan Chen and Podojil, {Joseph R.} and Robinson, {Andrew P.} and Roumen Balabanov and Brian Popko and Miller, {Stephen D.}",
note = "Funding Information: Relevant work in the authors{\textquoteright} laboratories has been supported by grants from the NIH [NS099334 and AI142059 (SDM), NS034939, NS109372, and NS067550 (BP)], the National Multiple Sclerosis Society [RG 4952-A-5 (SDM and BP)], the Myelin Repair Foundation (SDM and BP), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (BP), the Rampy MS Research Foundation (BP), the Johnnie Walker{\textquoteright}s MS Foundation (SDM), the David and Amy Fulton Foundation (SDM), the Cramer Family Foundation (SDM), and a National Multiple Sclerosis Society Postdoctoral Fellowship FG 20125-A-1 (HET). Funding Information: Weiner, H. L. (2009). The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann. Neurol. 65, 239–248. doi: 10.1002/ana.21640 Weller, M., Liedtke, W., Petersen, D., Opitz, H., and Poremba, M. (1992). Very-late-onset adrenoleukodystrophy: possible precipitation of demyelination by cerebral contusion. Neurology 42, 367–370. doi: 10.1212/wnl.42.2.367 Wetzig, R., Hanson, D. G., Miller, S. D., and Claman, H. N. (1979). Binding of ovalbumin to mouse spleen cells with and without carbodiimide. J. Immunol. Methods 28, 361–368. doi: 10.1016/0022-1759(79)90201-1 Windhagen, A., Newcombe, J., Dangond, F., Strand, C., Woodroofe, M. N., Cuzner, M. L., et al. (1995). Expression of costimulatory molecules B7-1 (CD80). B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J. Exp. Med. 182, 1985–1996. doi: 10.1084/jem.182.6.1985 Wioland, L., Dupont, J. L., Doussau, F., Gaillard, S., Heid, F., Isope, P., et al. (2015). Epsilon toxin from Clostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination. Cell Microbiol. 17, 369–388. doi: 10.1111/cmi.12373 Wood, D. D., Bilbao, J. M., O{\textquoteright}connors, P., and Moscarello, M. A. (1996). Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. Ann. Neurol. 40, 18–24. doi: 10.1002/ana.41040 0106 Yadav, S. K., Soin, D., Ito, K., and Dhib-Jalbut, S. (2019). Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis. J. Mol. Med. 97, 463–472. doi: 10.1007/s00109-019-01761-5 Zarrouk, A., Nury, T., Karym, E. M., Vejux, A., Sghaier, R., Gondcaille, C., et al. (2017). Attenuation of 7-ketocholesterol-induced overproduction of reactive oxygen species, apoptosis, and autophagy by dimethyl fumarate on 158N murine oligodendrocytes. J. Steroid. Biochem. Mol. Biol. 169, 29–38. doi: 10. 1016/j.jsbmb.2016.02.024 Zhang, J., Zhang, Z. G., Li, Y., Ding, X., Shang, X., Lu, M., et al. (2015). Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis. Neurobiol. Dis. 76, 57–66. doi: 10.1016/j.nbd.2015.01.006 Zhang, Y., Burger, D., Saruhan, G., Jeannet, M., and Steck, A. J. (1993). The T-lymphocyte response against myelin-associated glycoprotein and myelin basic protein in patients with multiple sclerosis. Neurology 43, 403–407. doi: 10.1212/wnl.43.2.403 Zrzavy, T., Hametner, S., Wimmer, I., Butovsky, O., Weiner, H. L., and Lassmann, H. (2017). Loss of {\textquoteleft}homeostatic{\textquoteright} microglia and patterns of their activation in active multiple sclerosis. Brain 140, 1900–1913. doi: 10.1093/brain/awx113 Conflict of Interest: SDM is an academic co-founder, scientific advisory board member, paid consultant, and grantee of Cour Pharmaceutical Development Company, Inc; scientific advisory board member and grantee of NextCure, Inc., scientific advisory board member of Takeda Pharmaceutical Company and Myeloid Therapeutics. RB has received honorariums and research support from Biogen, Sanofi Genzyme, Genentech, and Alexion Pharmaceuticals, Inc. JP was employed by company Cour Pharmaceutical Development Company, Inc.",
year = "2020",
month = oct,
day = "27",
doi = "10.3389/fncel.2020.599717",
language = "English (US)",
volume = "14",
journal = "Frontiers in Cellular Neuroscience",
issn = "1662-5102",
publisher = "Frontiers Research Foundation",
}