Modele doświadczalne stwardnienia rozsianego

• Authors: Izabela Jatczak , Andrzej Głąbiński

Title variants

EN

Experimental models of multiple sclerosis

• Languages of publication: EN PL

Abstracts

EN

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Aetiology of SM is still unknown. Two pathological processes: inflammation and neurodegeneration are present from the beginning of MS. Autoreactive myelin-specific T cells can mediate the inflammatory response. Final stage of the development of MS is demyelination and axonal damage, which leads to the appearance of neurological symptoms. Several experimental models of MS were developed to get information about the mechanisms of the disease development. Those models include knockout mice (known as myelin mutants), chemically induced inflammation in the CNS, viral and autoimmune models. Knockout animals with blocked gene for myelin basic protein (MBP), mice Rumpshaker and Jimpy without genes for proteolipid protein (PLP), and mice with blocked gene for myelin associated glycoprotein (MAG) have been used to study the mechanisms of demyelination. The use of various toxins such as ethidium bromide or cuprizone also allows the study of the mechanisms of de-/remyelinization in the CNS. Viral models of MS can be induced by Semliki Forest virus and Theiler’s virus. The well-known and widely used experimental model of MS is experimental autoimmune encephalomyelitis (EAE). None of the mentioned above models perfectly initiate development and course of this disease. However, thanks to them the pathological mechanisms leading to development of MS can be studied.

PL

Stwardnienie rozsiane (łac. sclerosis multiplex, SM) jest przewlekłą chorobą ośrodkowego układu nerwowego (OUN) o podłożu autoimmunologicznym. Etiologia SM wciąż nie jest poznana. Od początku choroby zachodzą w OUN dwa procesy patologiczne: zapalenie i neurodegeneracja. W reakcji zapalnej pośredniczą autoreaktywne mielinowoswoiste limfocyty T. Końcowym etapem rozwoju SM jest demielinizacja i zniszczenie aksonów, co doprowadza do zaburzeń neurologicznych. Aby zdobyć informacje o mechanizmach rozwoju SM, często wykorzystuje się różne modele doświadczalne tej choroby. Wśród tych modeli należy wymienić myszy knockout (tzw. mutanty mielinowe), chemicznie indukowane w OUN zmiany zapalne i wirusowe oraz modele autoimmunizacyjne. Do zwierząt knockout, umożliwiających poznawanie mechanizmów demielinizacji, zaliczamy m.in. myszy Shiverer pozbawione genów dla białka zasadowego mieliny (MBP), myszy Rumpshaker i Jimpy bez genów dla lipofiliny (PLP) oraz myszy bez glikoproteiny związanej z mieliną (MAG). Użycie różnych toksyn, takich jak kuprizon czy bromek etydyny, również umożliwia badanie mechanizmów powstawania de-/remielinizacji w OUN. Do wirusowych modeli SM zaliczamy modele wywołane wirusem Semliki Forest i wirusem Theilera. Najbardziej znanym i szeroko używanym doświadczalnym modelem zwierzęcym SM jest doświadczalne autoimmunizacyjne zapalenie mózgu i rdzenia kręgowego (EAE). Żaden z wymienionych powyżej modeli nie naśladuje wiernie powstawania i przebiegu tej choroby. Mimo to możemy dzięki nim poznawać mechanizmy regulacji odpowiedzi immunologicznej, które w przyszłości mogą być podstawą do opracowania nowych, skutecznych metod farmakologicznego leczenia SM i innych podobnych chorób.

Keywords

EN

Theiler’s murine encephalomyelitis virus (TMEV); demielinizacja; demyelination; doświadczalne autoimmunizacyjne zapalenie mózgu i rdzenia kręgowego; experimental autoimmune encephalomyelitis (EAE); experimental models; modele doświadczalne; multiple sclerosis; stwardnienie rozsiane; wirus Theilera

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Aktualności Neurologiczne
• Year: 2009
• Volume: 9
• Issue: 4
• Pages: 231-239

Contributors

author

Izabela Jatczak

• Oddział Kliniczny Propedeutyki Neurologicznej, Uniwersytet Medyczny w Łodzi

author

Andrzej Głąbiński

• Oddział Kliniczny Propedeutyki Neurologicznej, Uniwersytet Medyczny w Łodzi

References

• 1. Fernando K.T., McLean M.A., Chard D.T. i wsp.: Elevated white matter myo-inositol in clinically isolated syndromes suggestive of multiple sclerosis. Brain 2004; 127: 1361-1369.
• 2. Ranjeva J.P., Pelletier J., Confort-Gouny S. i wsp.: MRI/ MRS of corpus callosum in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult. Scler. 2003; 9: 554-565.
• 3. Zivadinov R., Bakshi R.: Role of MRI in multiple sclerosis I: inflammation and lesions. Front. Biosci. 2004; 9: 665-683.
• 4. Rodriguez M., Lucchinetti C.F.: Is apoptotic death of the oligodendrocyte a critical event in the pathogenesis of multiple sclerosis? Neurology 1999; 53: 1615-1616.
• 5. Steinman L.: Multiple sclerosis: a two-stage disease. Nat. Immunol. 2001; 2: 762-764.
• 6. Lassmann H.: New concepts on progressive multiple sclerosis. Curr. Neurol. Neurosci. Rep. 2007; 7: 239-244.
• 7. Hickey WF., Cohen J.A., Burns J.B.: A quantitative immunohistochemical comparison of actively versus adoptively induced experimental allergic encephalomyelitis in the Lewis rat. Cell. Immunol. 1987; 109: 272-281.
• 8. Bjartmar C., Trapp B.D.: Axonal degeneration and progressive neurologic disability in multiple sclerosis. Neurotox. Res. 2003; 5: 157-164.
• 9. Bø L., Vedeler C.A., Nyland H. i wsp.: Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult. Scler. 2003; 9: 323-331.
• 10. Cross A.H., Tuohy VK., Raine C.S.: Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell. Immunol. 1993; 146: 261-269.
• 11. Lehmann P.V., Forsthuber T., Miller A., Sercarz E.E.: Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992; 358: 155-157.
• 12. Mor F., Cohen I.R.: Shifts in the epitopes of myelin basic protein recognized by Lewis rat T cells before, during, and after the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 1993; 92: 2199-2206.
• 13. Perry L.L., Barzaga-Gilbert E., Trotter J.L.: T cell sensitization to proteolipid protein in myelin basic protein-induced relapsing experimental allergic encephalomyelitis. J. Neuroimmunol. 1991; 33: 7-15.
• 14. Alpérovitch A., Berr C., Cambon-Thomsen A. i wsp.: Viral antibody titers, immunogenetic markers, and their interrelations in multiple sclerosis patients and controls. Hum. Immunol. 1991; 31: 94-99.
• 15. Fujinami R.S., Oldstone M.B., Wroblewska Z. i wsp.: Molecular mimicry in virus infection: crossreaction of measles virus phosphoprotein or of herpes simplex virus protein with human intermediate filaments. Proc. Natl Acad. Sci. USA 1983; 80: 2346-2350.
• 16. Zabriskie J.B.: Rheumatic fever: a model for the pathological consequences of microbial-host mimicry. Clin. Exp. Rheumatol. 1986; 4: 65-73.
• 17. Fujinami R.S., Oldstone M.B.: Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985; 230: 1043-1045.
• 18. Croxford J.L., Anger H.A., Miller S.D.: Viral delivery of an epitope from Haemophilus influenzae induces central nervous system autoimmune disease by molecular mimicry. J. Immunol. 2005; 174: 907-917.
• 19. Lang H.L., Jacobsen H., Ikemizu S. i wsp.: A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 2002; 3: 940-943.
• 20. Markovic-Plese S., McFarland H.F.: Immunopathogenesis of the multiple sclerosis lesion. Curr. Neurol. Neurosci. Rep. 2001; 1: 257-262.
• 21. Sospedra M., Zhao Y., zur Hausen H. i wsp.: Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity. PLoS Pathog. 2005; 1: e41.
• 22. Sriram S., Stratton C.W, Yao S. i wsp.: Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann. Neurol. 1999; 46: 6-14.
• 23. Tejada-Simon M.V, Zang Y.C., Hong J. i wsp.: Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann. Neurol. 2003; 53: 189-197.
• 24. Nave K.A.: Neurological mouse mutants and the genes of myelin. J. Neurosci. Res. 1994; 38: 607-612.
• 25. Readhead C., Hood L.: The dysmyelinating mouse mutations shiverer (shi) and myelin deficient (shimld). Behav. Genet. 1990; 20: 213-234.
• 26. Fanarraga M.L., Griffiths I.R., McCulloch M.C. i wsp.: Rumpshaker: an X-linked mutation causing hypomyelination: developmental differences in myelination and glial cells between the optic nerve and spinal cord. Glia 1992; 5: 161-170.
• 27. Griffiths I.R., Scott I., McCulloch M.C. i wsp.: Rumpshaker mouse: a new X-linked mutation affecting myelination: evidence for a defect in PLP expression. J. Neurocytol. 1990; 19: 273-283.
• 28. Edgar J.M., McLaughlin M., Barrie J.A. i wsp.: Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene. Acta Neuropathol. 2004; 107: 331-335.
• 29. Phillips R.J.: Jimpy, a new totally sexlinked gene in the house mouse. Z. Indukt. Abstamm. Vererbungsl. 1954; 86: 322-326.
• 30. Boison D., Bussow H., D’Urso D. i wsp.: Adhesive properties of proteolipid protein are responsible for the compaction of CNS myelin sheaths. J. Neurosci. 1995; 15: 5502-5513.
• 31. Knapp P.E., Skoff R.P., Redstone D.W: Oligodendroglial cell death in jimpy mice: an explanation for the myelin deficit. J. Neurosci. 1986; 6: 2813-2822.
• 32. Duncan I.D., Hammang J.P., Goda S., Quarles R.H.: Myelination in the jimpy mouse in the absence of proteolipid protein. Glia 1989; 2: 148-154.
• 33. Robain O.: The jimpy mouse. Acta Zool. Pathol. Antverp. 1977; (68): 68-92.
• 34. Rosenfeld J., Freidrich VL. Jr: Axonal swellings in jimpy mice: does lack of myelin cause neuronal abnormalities? Neuroscience 1983; 10: 959-966.
• 35. Farkas-Bargeton E., Robain O., Mandel P.: Abnormal glial maturation in the white matter in Jimpy mice. An optical study. Acta Neuropathol. 1972; 21: 272-281.
• 36. Jacque C., Lachapelle F., Collier P. i wsp.: Accumulation of GFA, the monomeric precursor of the gliofilaments, during development in normal mice and dysmyelinating mutants. J. Neurosci. Res. 1980; 5: 379-385.
• 37. Trapp B.D.: Myelin-associated glycoprotein. Location and potential functions. Ann. N. Y. Acad. Sci. 1990; 605: 29-43.
• 38. Bartsch U., Kirchhoff F., Schachner M.: Immunohistological localization of the adhesion molecules L1, N-CAM, and MAG in the developing and adult optic nerve of mice. J. Comp. Neurol. 1989; 284: 451-462.
• 39. Owens G.C., Bunge R.P.: Evidence for an early role for myelin-associated glycoprotein in the process of myelination. Glia 1989; 2: 119-128.
• 40. Trapp B.D., Andrews S.B., Cootauco C., Quarles R.: The myelin-associated glycoprotein is enriched in multivesicular bodies and periaxonal membranes of actively myelinating oligodendrocytes. J. Cell Biol. 1989; 109: 2417-2426.
• 41. Montag D., Giese K.P., Bartsch U. i wsp.: Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 1994; 13: 229-246.
• 42. Schachner M., Bartsch U.: Multiple functions of the myelin-associated glycoprotein MAG (siglec-4a) in formation and maintenance of myelin. Glia 2000; 29: 154-165.
• 43. Yajima K., Suzuki K.: Demyelination and remyelination in the rat central nervous system following ethidium bromide injection. Lab. Invest. 1979; 41: 385-392.
• 44. Hiremath M.M., Saito Y., Knapp G.W i wsp.: Microglial/ macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J. Neuroimmunol. 1998; 92: 38-49.
• 45. Love S.: Cuprizone neurotoxicity in the rat: morphologic observations. J. Neurol. Sci. 1988; 84: 223-237.
• 46. Ludwin S.K.: Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab. Invest. 1978; 39: 597-612.
• 47. McMahon E.J., Suzuki K., Matsushima G.K.: Peripheral macrophage recruitment in cuprizone-induced CNS demye-lination despite an intact blood-brain barrier. J. Neuroimmunol. 2002; 130: 32-45.
• 48. Mathiot C.C., Grimaud G., Garry P. i wsp.: An outbreak of human Semliki Forest virus infections in Central African Republic. Am. J. Trop. Med. Hyg. 1990; 42: 386-393.
• 49. Atkins G.J., Sheahan B.J., Dimmock N.J.: Semliki Forest virus infection of mice: a model for genetic and molecular analysis of viral pathogenicity. J. Gen. Virol. 1985; 66: 395-408.
• 50. Fazakerley J.K., Buchmeier M.J.: Pathogenesis of virus-induced demyelination. Adv. Virus Res. 1993; 42: 249-324.
• 51. Fazakerley J.K., Walker R.: Virus demyelination. J. Neurovi-rol. 2003; 9: 148-164.
• 52. Barrett P.N., Sheahan B.J., Atkins G.J.: Isolation and preliminary characterization of Semliki Forest virus mutants with altered virulence. J. Gen. Virol. 1980; 49: 141-147.
• 53. Pusztai R., Gould E.A., Smith H.: Infection patterns in mice of an avirulent and virulent strain of Semliki Forest virus. Br. J. Exp. Pathol. 1971; 52: 669-677.
• 54. Donnelly S.M., Sheahan B.J., Atkins G.J.: Long-term effects of Semliki Forest virus infection in the mouse central nervous system. Neuropathol. Appl. Neurobiol. 1997; 23: 235-241.
• 55. Parsons L.M., Webb H.E.: Virus titres and persistently raised white cell counts in cerebrospinal fluid in mice after peripheral infection with demyelinating Semliki Forest virus. Neuropathol. Appl. Neurobiol. 1982; 8: 395-401.
• 56. Morris M.M., Dyson H., Baker D. i wsp.: Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection. J. Neuroimmunol. 1997; 74: 185-197.
• 57. Subak-Sharpe I., Dyson H., Fazakerley J.: In vivo depletion of CD8+ T cells prevents lesions of demyelination in Semliki Forest virus infection. J. Virol. 1993; 67: 7629-7633.
• 58. Tremain K.E., Ikeda H.: Physiological deficits in the visual system of mice infected with Semliki Forest virus and their correlation with those seen in patients with demyelinating disease. Brain 1983; 106: 879-895.
• 59. Bendiner E.: Max Theiler: yellow jack and the jackpot. Hosp. Pract. (Off. Ed.) 1988; 23: 211-212, 214-215, 219-222 passim.
• 60. Theiler M.: Spontaneous encephalomyelitis of mice - a new virus disease. Science 1934; 80: 122.
• 61. Tsunoda I., Iwasaki Y., Terunuma H. i wsp.: A comparative study of acute and chronic diseases induced by two subgroups of Theiler’s murine encephalomyelitis virus. Acta Neuropathol. 1996; 91: 595-602.
• 62. Knobler R.L., Rodriguez M., Lampert P.W, Oldstone M.B.: Virologic models of chronic relapsing demyelinating disease. Acta Neuropathol. Suppl. 1983; 9: 31-37.
• 63. Rodriguez M.: Virus-induced demyelination in mice: “dying back” of oligodendrocytes. Mayo Clin. Proc. 1985; 60: 433-438.
• 64. Monteyne P., Bureau J.F., Brahic M.: The infection of mouse by Theiler’s virus: from genetics to immunology. Immunol. Rev. 1997; 159: 163-176.
• 65. Tsunoda I., Fujinami R.S.: Two models for multiple sclerosis: experimental allergic encephalomyelitis and Theiler’s murine encephalomyelitis virus. J. Neuropathol. Exp. Neurol. 1996; 55: 673-686.
• 66. Tsunoda I., Fujinami R.S.: Inside-Out versus Outside-In models for virus induced demyelination: axonal damage triggering demyelination. Springer Semin. Immunopathol. 2002; 24: 105-125.
• 67. Lublin F.D., Reingold S.C.: Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46: 907-911.
• 68. Tsunoda I., Kuang L.Q., Theil D.J., Fujinami R.S.: Antibody association with a novel model for primary progressive multiple sclerosis: induction of relapsing-remitting and progressive forms of EAE in H2s mouse strains. Brain Pathol. 2000; 10: 402-418.
• 69. Tolley N.D., Tsunoda I., Fujinami R.S.: DNA vaccination against Theiler’s murine encephalomyelitis virus leads to alterations in demyelinating disease. J. Virol. 1999; 73: 993-1000.
• 70. Watanabe R., Wege H., ter Meulen V: Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis. Nature 1983; 305: 150-153.
• 71. Barbano R.L., Dal Canto M.C.: Serum and cells from Theiler’s virus-infected mice fail to injure myelinating cultures or to produce in vivo transfer of disease. The pathogenesis of Theiler’s virus-induced demyelination appears to differ from that of EAE. J. Neurol. Sci. 1984; 66: 283-293.
• 72. Broytman O., Malter J.S.: Anti-Aβ: the good, the bad, and the unforeseen. J. Neurosci. Res. 2004; 75: 301-306.
• 73. Rivers T.M., Sprunt D.H., Berry G.P.: Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 1933; 58: 39-53.
• 74. Kabat E.A., Wolf A., Bezer A.E.: The rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of heterologous and homologous brain tissue with adjuvants. J. Exp. Med. 1947; 85: 117-130.
• 75. Morgan I.M.: Allergic encephalomyelitis in monkeys in response to injection of normal monkey nervous tissue. J. Exp. Med. 1947; 85: 131-140.
• 76. Glabinski A.R., Tani M., Tuohy VK., Ransohoff R.M.: Murine experimental autoimmune encephalomyelitis: a model of immune-mediated inflammation and multiple sclerosis. Methods Enzymol. 1997; 288: 182-190.
• 77. Amiguet P., Gardinier M.V, Zanetta J.P., Matthieu J.M.: Purification and partial structural and functional characterization of mouse myelin/oligodendrocyte glycoprotein. J. Neurochem. 1992; 58: 1676-1682.
• 78. Bischof F., Bins A., Durr M. i wsp.: A structurally available encephalitogenic epitope of myelin oligodendrocyte glycoprotein specifically induces a diversified pathogenic autoimmune response. J. Immunol. 2004; 173: 600-606.
• 79. Schluesener H.J., Sobel R.A., Linington C., Weiner H.L.: A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J. Immunol. 1987; 139: 4016-4021.
• 80. Koehler N.K., Genain C.P., Giesser B., Hauser S.L.: The human T cell response to myelin oligodendrocyte glycoprotein: a multiple sclerosis family-based study. J. Immunol. 2002; 168: 5920-5927.
• 81. Brehm U., Piddlesden S.J., Gardinier M.V, Linington C.: Epitope specificity of demyelinating monoclonal autoantibodies directed against the human myelin oligodendrocyte glycoprotein (MOG). J. Neuroimmunol. 1999; 97: 9-15.
• 82. Morris-Downes M.M., Smith P.A., Rundle J.L. i wsp.: Pathological and regulatory effects of anti-myelin antibodies in experimental allergic encephalomyelitis in mice. J. Neuroimmunol. 2002; 125: 114-124.
• 83. Huseby E.S., Liggitt D., Brabb T. i wsp.: A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis. J. Exp. Med. 2001; 194: 669-676.
• 84. Sun D., Whitaker J.N., Huang Z. i wsp.: Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J. Immunol. 2001; 166: 75797587.
• 85. Brunner C., Lassmann H., Waehneldt T.V i wsp.: Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2’,3’-cyclic nucleotide 3’-phosphodiesterase in the CNS of adult rats. J. Neurochem. 1989; 52: 296-304.
• 86. Linker R.A., Gold R.: MBP-induced experimental autoimmune encephalomyelitis in C57BL/6 mice. J. Immunol. 2004; 173: 2896.
• 87. Kent S.J., Karlik S.J., Cannon C. i wsp.: A monoclonal antibody to α4 integrin suppresses and reverses active experimental allergic encephalomyelitis. J. Neuroimmunol. 1995; 58: 1-10.
• 88. Pettinelli C.B., Fritz R.B., Chou C.H., McFarlin D.E.: Encephalitogenic activity of guinea pig myelin basic protein in the SJL mouse. J. Immunol. 1982; 129: 1209-1211.
• 89. Rösener M., Muraro P.A., Riethmüller A. i wsp.: 2’,3’-cyclic nucleotide 3’-phosphodiesterase: a novel candidate autoantigen in demyelinating diseases. J. Neuroimmunol. 1997; 75: 28-34.
• 90. Kojima K., Berger T., Lassmann H. i wsp.: Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100β molecule, a calcium binding protein of astroglia. J. Exp. Med. 1994; 180: 817-829.
• 91. Mokhtarian F., McFarlin D.E., Raine C.S.: Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature 1984; 309: 356-358.
• 92. Pettinelli C.B., McFarlin D.E.: Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2- T lymphocytes. J. Immunol. 1981; 127: 1420-1423.
• 93. Hickey W.F.: Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol. 1991; 1: 97-105.
• 94. Hickey WF, Hsu B.L., Kimura H.: T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 1991; 28: 254-260.
• 95. Hickey WF.: Leukocyte traffic in the central nervous system: the participants and their roles. Semin. Immunol. 1999; 11: 125-137.
• 96. Tran E.H., Hoekstra K., van Rooijen N. i wsp.: Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J. Immunol. 1998; 161: 3767-3775.
• 97. Hauser S.L., Bhan A.K., Gilles F. i wsp.: Immunohistochem-ical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann. Neurol. 1986; 19: 578-587.
• 98. Lassmann H., Ransohoff R.M.: The CD4-Th1 model for multiple sclerosis: a critical [correction of crucial] reappraisal. Trends Immunol. 2004; 25: 132-137.
• 99. Van der Aa A., Hellings N., Bernard C.C. i wsp.: Functional properties of myelin oligodendrocyte glycoprotein-reactive T cells in multiple sclerosis patients and controls. J. Neuroimmunol. 2003; 137: 164-176.
• 100. Gold R., Linington C., Lassmann H.: Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 2006; 129: 1953-1971.
• 101. Ransohoff R.M.: EAE: pitfalls outweigh virtues of screening potential treatments for multiple sclerosis. Trends Immunol. 2006; 27: 167-168.
• 102. Sriram S., Steiner I.: Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann. Neurol. 2005; 58: 939-945.
• 103. Steinman L., Zamvil S.S.: How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann. Neurol. 2006; 60: 12-21.
• 104. Lisak R.P., Zweiman B., Blanchard N., Rorke L.B.: Effect of treatment with Copolymer 1 (Cop-1) on the in vivo and in vitro manifestations of experimental allergic encephalomyelitis (EAE). J. Neurol. Sci. 1983; 62: 281-293.
• 105. Munari L., Lovati R., Boiko A.: Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst. Rev. 2004; (1): CD004678.

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