Journal of Neurology

, Volume 251, Issue 11, pp 1304–1316 | Cite as

The neuroprotective role of inflammation in nervous system Injuries



The contribution of inflammation to the pathogenesis of several nervous system disorders has long been established. Other observations, however, indicate that both inflammatory cells and mediators may also have beneficial functions, assisting in repair and recovery processes. There is compelling evidence to indicate that in the injured nervous system, as in other tissues, macrophages are needed at an early stage after injury in order for healing to take place. Likewise, activated T cells of a particular specificity can reduce the spread of damage. This neuroprotective effect of T cells may be caused, at least in part, by the production of neurotrophic factors such as neurotrophin-3 or brain-derived neurotrophic factor. Interestingly, recent findings indicate that immune cells are able to produce a variety of neurotrophic factors which promote neuronal survival and may also mediate anti-inflammatory effects. Numerous cytokines are induced after nervous system injuries. Some cytokines, such as TNF-α, IL-1 and IFN-γ, are well known for their promotion of inflammatory responses. However, these cytokines also have immunosuppressive functions and their subsequent expression also assists in repair or recovery processes, suggesting a dual role for some pro-inflammatory cytokines. This should be clarified, as it may be crucial in the design of therapeutic strategies to target specific cytokine(s). Finally, there is a growing body of evidence to show that autoreactive IgM antibodies may constitute an endogenous system of tissue repair, and therefore prove of value as a therapeutic strategy. Available evidence would appear to indicate that the inflammatory response observed in several neurological conditions is more complex than previously thought. Therefore, the design of more effective therapies depends on a clear delineation of the beneficial and detrimental effects of inflammation.

Key words

neuroprotection macrophages T cells cytokines antibodies 


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  1. 1.
    Albrecht PJ, Dahl JP, Stoltzfus OK, Levenson R, Levinson SW (2002) Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Exp Neurol 173:46–62PubMedGoogle Scholar
  2. 2.
    Alexander WS, Starr R, Fenner JE, Scott CL, Handmann E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczareck CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ (1999) SOCS1 is a critical inhibitor of interferon gamma signalling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597–608PubMedGoogle Scholar
  3. 3.
    Aloisi F, Borsellino G, Samoggia P, Testa U, Chelucci C, Russo G, Peschle C, Levi G (1992). Astrocyte cultures from human embryonic brain: characterization and modulation of surface molecules by inflammatory cytokines. J Neurosci Res 32:494–506PubMedGoogle Scholar
  4. 4.
    Aloisi F, Ria F, Penna G, Adorini L (1998) Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation. J Immunol 160:4671–4680PubMedGoogle Scholar
  5. 5.
    Aloisi F, Penna G, Polazzi E, Minghetti L,Adorini L (1999) CD40-CD154 interaction and IFN-gamma are required for IL-12 but not prostaglandin E2 secretion by microglia during antigen presentation to Th1 cells (1999). J Immunol 162:1384–1391PubMedGoogle Scholar
  6. 6.
    Antel JP, Becher B (1998) Central nervous system—Immune interactions: Contribution to neurologic disease and recovery. In: Antel J, Birnbaum G, Hartung HP (eds) Clinical Neuroimmunology. Blackwell Science, Oxford, pp 26–39Google Scholar
  7. 7.
    Antel J, Birnbaum G, Hartung HP (1998) Clinical Neuroimmunology. Blackwell Science, OxfordGoogle Scholar
  8. 8.
    Armati PJ, Pollard JD, Gatenby P (1990) Rat and human Schwann cells in vitro can synthesize and express MHC molecules. Muscle Nerve 13:106–116PubMedGoogle Scholar
  9. 9.
    Arnett HA, Masson J, Marino M, Suzuki K, Matsushima GK, Ting JPY (2001) TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neurosci 4:1116–1122PubMedGoogle Scholar
  10. 10.
    Arnett HA, Wang Y, Matsushima GK, Suzuki K, Ting JPY (2003) Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocytes regeneration. J Neurosci 23:9824–9832PubMedGoogle Scholar
  11. 11.
    Asada H, Ip NY, Pan L, Razack N, Parfitt MM, Plunkett RJ (1995) Time course of ciliary neurotrophic factor mRNA expression is coincident with the presence of protoplasmic astrocytes in traumatized rat striatum. J Neurosci Res 40:22–30PubMedGoogle Scholar
  12. 12.
    Asakura K, Miller DJ, Murray P, Bansal R, Pfeiffer SE, Rodriguez M (1996) Monoclonal autoantibody SCH94.03, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res 43:273–281PubMedGoogle Scholar
  13. 13.
    Asakura K, Miller DJ, Pease LR, Rodriguez M (1998) Targeting of IgMκ antibodies to oligodendrocytes promotes CNS remyelination. J Neurosci 18:7700–7708PubMedGoogle Scholar
  14. 14.
    Asakura K, Rodriguez M (1998) A unique population of circulating autoantibodies promotes central nervous system remyelination. Mult Scler 4:217–221PubMedGoogle Scholar
  15. 15.
    Bai XF, Zhu J, Zhang GX, Kaponides G, Hojeberg B, van der Meide PH, Link H (1997) IL-10 suppresses experimental autoimmune neuritis and downregulates cytokine mRNA expression of Th1 and macrophage source. Clin Immunol Immunopathol 83:117–126PubMedGoogle Scholar
  16. 16.
    Baloh RH, Enomoto H, Johnson EM Jr, Milbrandt J (2000) The GDNF family ligands and receptors-implications for neural development. Curr Opin Neurobiol 10:103–110Google Scholar
  17. 17.
    Barde YA, Edgar D, Thoenen H (1983) New neurotrophic factors. Annu Rev Physiol 45:601–612PubMedGoogle Scholar
  18. 18.
    Barouch R, Appel E, Kazimirsky G, Brodie C (2001) Macrophages express neurotrophins and neurotrophin receptors. Regulation of nitric oxide production by NT-3. J Neuroimmunol 112:72–77PubMedGoogle Scholar
  19. 19.
    Barouch R, Schwartz M (2002) Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: Implications for protective autoimmunity. FASEB J 16:1304–1306PubMedGoogle Scholar
  20. 20.
    Batchelor PE, Liberatore GT, Wong JYF, Porrit MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19:1708–1716PubMedGoogle Scholar
  21. 21.
    Becher B, Antel JP (1996) Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia 18:1–10PubMedGoogle Scholar
  22. 22.
    Be’eri H, Reichert F, Saada A, Rotshenker S (1998) The cytokine network of wallerian degeneration: IL-10 and GM-CSF. Eur J Neurosci 10:2707–2713PubMedGoogle Scholar
  23. 23.
    Besser M, Wang R (1999) Clonally restricted production of the neurotrophin brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162:6303–6306PubMedGoogle Scholar
  24. 24.
    Bieber AJ, Warrington A, Asakura K, Ciric B, Kaveri SV, Pease LR, Rodriguez M (2002) Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia 37:241–249PubMedGoogle Scholar
  25. 25.
    Bieber AJ, Kerr S, Rodriguez M (2003) Efficient central nervous system remyelination requires T cells. Ann Neurol 53:680–684PubMedGoogle Scholar
  26. 26.
    Billiau A, Heremans H, Vandekerckhove F, Dijkmans R, Sobis H, Meulepas E, Carton H (1988) Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J Immunol 140:1506–1510PubMedGoogle Scholar
  27. 27.
    Burns J, Rosenzweig A, Zweiman B, Lisak RP (1983) Isolation of myelin basic protein-reactive T cell lines from normal human blood. Cell Immunol 81:435–440PubMedGoogle Scholar
  28. 28.
    Brück W, Huitinga I, Dijkstra CD (1996) Liposome-mediated monocyte depletion during Wallerian degeneration defines the role of hematogenous phagocytes in myelin removal. J Neurosci Res 46:477–484PubMedGoogle Scholar
  29. 29.
    Chaudhry V, Glass JD, Griffin JW (1992) Wallerian degeneration in peripheral nerve disease. Neurol Clin 10:613–627PubMedGoogle Scholar
  30. 30.
    Chen MS, Huber AB, van der Haar ME, Frank M, Scnell L, Spillman AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439CrossRefPubMedGoogle Scholar
  31. 31.
    Ciric B, Howe CL, Paz Soldan M, Warrington AE, Bieber AJ, van Keulen V, Rodriguez M, Pease LR (2003) Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function. Brain Pathol 13:608–616PubMedGoogle Scholar
  32. 32.
    Ciric B, Van Keulen V, Paz Soldan M, Rodriguez M, Pease LR (2004) Antibody-mediated remyelination operates through mechanism independent of immunomodulation. J Neuroimmunol 146:153–161PubMedGoogle Scholar
  33. 33.
    Correale J, McMillan M, McCarthy K, Le T, Weiner LP (1995) Isolation and characterization of autoreactive proteolipid protein-peptide specific T-cell clones from multiple sclerosis patients. Neurology 45:1370–1378PubMedGoogle Scholar
  34. 34.
    Correale J, Bassani Molinas MM (2002) Oligoclonal bands and antibody responses in Multiple Sclerosis. J Neurol 249:375–389PubMedGoogle Scholar
  35. 35.
    Cowley SA, Butter C, Gschmeissner SE, Curtis J, Turk JL (1989) An immuno-electromicroscopical study of the expression of major histocompatibility complex (MHC) class II antigens in guinea pig sciatic nerves following induction of intraneural mycobacterial granulomas. J Neuroimmunol 23:223–231PubMedGoogle Scholar
  36. 36.
    Creange A, Barlovatz-Meimon G, Gherardi RK (1997) Cytokines and peripheral nerve disorders. Eur Cytokine Netw 8:145–151PubMedGoogle Scholar
  37. 37.
    David S, Aguayo AJ (1981) Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:931–933PubMedGoogle Scholar
  38. 38.
    David S, Aguayo AJ (1985) Axonal regeneration after crush injury in rat central nervous system fibers innervating peripheral nerve grafts. J Neurocytol 14:1–12PubMedGoogle Scholar
  39. 39.
    David S, Bouchard C, Tsatas O, Giftochristos N (1990) Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron 5:463–469PubMedGoogle Scholar
  40. 40.
    Day WA, Kosihi K, McLennan IS (2003) Transforming growth factor beta 1 may regulate the stability of mature myelin sheath. Exp Neurol 184:857–864PubMedGoogle Scholar
  41. 41.
    Deller T, Haas CA, Naumann T, Joester A, Faissner A, Frotscher M (1997) Up-regulation of astrocyte-derived tenascin-C correlates with neurite out-growth in the rat dentate gyrus after unilateral entorhinal cortex lesion. Neuroscience 81:829–846PubMedGoogle Scholar
  42. 42.
    De Jong BA, Smith ME (1997) A role for complement in phagocytosis of myelin. Neurochem Res 22:491–498PubMedGoogle Scholar
  43. 43.
    De Kosky ST, Styren SD, O’Malley ME, Gross JR, Kochanek P, Marion D, Evans CH, Robbins PD (1996) Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain. Ann Neurol 39:123–127PubMedGoogle Scholar
  44. 44.
    Duong TT, St Louis J, Gilbert JJ, Finkelman FD, Strejan GH (1992) Effect of anti-interferon gamma and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental allergic encephalomyelitis in the SJL/J mouse. J Neuroimmunol 36:105–115PubMedGoogle Scholar
  45. 45.
    Dyer CA, Benjamins JA (1989) Organization of oligodendrocytes membrane sheets. II. Galactocerebroside: antibody interactions signal changes in cytoskeleton and myelin basic protein. J Neurosci Res 24:212–221PubMedGoogle Scholar
  46. 46.
    Dyer CA, Benjamins JA (1991) Galactocerebroside and sulfatide independently mediate Ca2+ responses in oligodendrocytes. J Neurosci Res 30:699–711PubMedGoogle Scholar
  47. 47.
    Dyer CA, Matthieu JM (1994) Antibodies to myelin/oligodendrocyte-specific protein and myelin/oligodendrocyte-specific glycoprotein signal distinct changes in the organization of cultured oligodendroglial membranes. J Neurochem 62:777–787PubMedGoogle Scholar
  48. 48.
    Ehrhard PB, Erb P, Garumann U, Otten U (1993) Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T cell clones. Proc Natl Acad Sci USA 90:10984–10988PubMedGoogle Scholar
  49. 49.
    Fernández-Valle C, Bunge RP, Bunge MB (1995) Schwann cells degrade myelin and proliferate in the absence of macrophages: evidence from in vitro studies of Wallerian degeneration. J Neurocytol 24:667–679PubMedGoogle Scholar
  50. 50.
    Flugel A, Matsumuro K, Neumann H, Klinkert WE, Birnbacher R, Lassmann H, Otten U, Wekerle H (2001) Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis inhibition of monocyte trans-endothelial migration. Eur J Immunol 31:11–22PubMedGoogle Scholar
  51. 51.
    Fontana A, Fierz F, Wekerle H (1994) Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature 307:273–276Google Scholar
  52. 52.
    Friedman B, Scherer SS, Rudge JS, Helgren M, Morriscy D, McIain J, Wang DY, Wiegand SJ, Furth ME, Lindsay RM (1992) Regulation of ciliary neurotrophic factor expression in myelinrelated Schwann cells in vivo. Neuron 9:295–305PubMedGoogle Scholar
  53. 53.
    Furlan R, Brambilla E, Ruffini F, Poliani PL, Bergami A, Marconi PC, Franciotta DM, Penna G, Comi G, Adorini L, Martino G (2001) Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes. J Immunol 167:1821–1829PubMedGoogle Scholar
  54. 54.
    George R, Griffin JW (1994) Delayed macrophage responses and myelin clearance during wallerian degeneration in the central nervous system: the dorsal radiculotomy model. Exp Neurol 129:225–236PubMedGoogle Scholar
  55. 55.
    Giulian D, Baker TJ, Shih LC, Lachman LB (1986) Interleukin 1 of the central nervous system is produced by ameboid microglia. J Exp Med 164:594–604PubMedGoogle Scholar
  56. 56.
    Giulian D, Woodward J, Young DG, Krebs JF, Lachman LB (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J Neurosci 8:2485–2490PubMedGoogle Scholar
  57. 57.
    Gold T, Toyka KV, Hartung HP (1995) Synergistic effect of IFN-gamma and TNF-alpha on expression of immune molecules and antigen presentation by Schwann cells. Cell Immunol 165:65–70PubMedGoogle Scholar
  58. 58.
    Griffin JW, Stoll G, Li CY, Tyor W, Cornblath DR (1990) Macrophage responses in demyelinating neuropathies. Ann Neurol 27:S64–S68PubMedGoogle Scholar
  59. 59.
    Griffin JW, Li CY, Ho TW, Tian M, Gao CY, Xue P, Mishu B, Cornblath DR, Macko C, McKhann GM, Asbury AK (1996) Pathology of the motor-sensory axonal Guillain-Barré. Ann Neurol 39:17–28PubMedGoogle Scholar
  60. 60.
    Grothe C, Meisinger C, Claus P (2001) In vivo expression and localization of the fibroblast growth factor system in the intact and lesioned rat peripheral nerve and spinal ganglia. J Comp Neurol 434:342–357PubMedGoogle Scholar
  61. 61.
    Guenard V, Dinarello CA, Weston PJ, Aebischer P (1991) Peripheral nerve regeneration is impeded by interleukin-1 receptor antagonist released from a polymeric guidance channel. J Neurosc Res 29:396–400Google Scholar
  62. 62.
    Guillen C, Jander S, Stoll G (1998) Sequential expression of mRNA for proinflammatory cytokines and interleukin-10 in the rat peripheral nervous system: comparison between immune-mediated demyelination and Wallerian degeneration. J Neurosci Res 51:489–496PubMedGoogle Scholar
  63. 63.
    Hagg T, Varon S (1993) Ciliary neurotrophic factor prevents degeneration of adult rats substantia nigra dopaminergic neurons in vivo. Proc Natl Acad Sci 90:6315–6319PubMedGoogle Scholar
  64. 64.
    Hammarberg H, Lidman O, Lundberg C, Eltayeb SY, Gielen AW, Muhallab S, Svenningsson A, Lindå H, van der Meide PH, Culheim S, Olsson T, Piehl F (2000) Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci 20:5283–5291PubMedGoogle Scholar
  65. 65.
    Hartung HP, Schafer B, van der Meide PH, Fierz W, Heininger K, Toyka KV (1990) The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system. Ann Neurol 27:247–257PubMedGoogle Scholar
  66. 66.
    Hattori A, Iwasaki S, Murase K, Tsujimoto M, Sato M, Hayashi K, Khono M (1994) Tumor necrosis factor is markedly synergistic with interleukin 1 and interferon-γ in stimulating the production of nerve growth factor in fibroblasts. FEBS Letters 340:177–180PubMedGoogle Scholar
  67. 67.
    Hauben E, Nevo U, Yoles E, Moaleem G, Agranov E, Mor F, Akselrod S, Neeman M, Cohen IR, Schwartz M (2000) Autoimmune T cells as potential neuroprotective therapy for spinal cord injury. Lancet 355:286–287PubMedGoogle Scholar
  68. 68.
    Hauben E, Gothilf A, Cohen A, Butovsky O, Nevo U, Smirnov I, Yoles E, Akselrod S, Schwartz M (2003) Vaccination with dendritic cells pulsed with peptides of myelin basic protein promotes functional recovery from spinal cord injury. J Neurosci 23:8808–8819PubMedGoogle Scholar
  69. 69.
    Henderson CE, Phillips HS, Pollock RA, Davies Am, Lemeulle C, Armanini M, Simpson LC, MoVet B, Vandlen RA, Koliatsos VE, Rosenthal A (1994) GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266:1062–1064PubMedGoogle Scholar
  70. 70.
    Herx LM, Rivest S, Yong VW (2000) Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1β is required for the production of ciliary neurotrophic factor. J Immunol 165:2232–2239Google Scholar
  71. 71.
    Heumann R, Korsching S, Bandtlow C, Thoenen H (1987) Changes of nerve growth factor synthesis in non neuronal cells response to sciatic nerve transection. J Cell Biol 104:1623–1631PubMedGoogle Scholar
  72. 72.
    Ho A, Blum M (1997) Regulation of astroglial-derived dopaminergic neurotrophic factors by interleukin-1 beta in striatum of young and middle-aged mice. Exp Neurol 148:348–359PubMedGoogle Scholar
  73. 73.
    Howe CL, Bieber AJ, Warrington AE, Pease LR, Rodriguez M (2004) Anti-apoptotic signalling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 15:120–131PubMedGoogle Scholar
  74. 74.
    Ip NY (1998) The neurotrophins and neuropoietic cytokines. Two families of growth factors acting on neural and hematopoietic cells. Ann N Y Acad Sci 840:97–106PubMedGoogle Scholar
  75. 75.
    Iseda T, Nishio T, Kawaguchi S, Yamanoto M, Kawasaki T, Wakisaka S (2004) Spontaneous regeneration of the corticospinal tract after transsection in young rats: a key role of reactive astrocytes in making favourable and unfavourable conditions for regeneration. Neuroscience 126:365–374PubMedGoogle Scholar
  76. 76.
    Jung S, Huitinga I, Schmidt B, Zielasek J, Dijkstra CD, Toyka KV, Hartung HP (1993) Selective elimination of macrophages by dichloromethylene diphosphonate-containing liposomes suppresses experimental autoimmune neuritis. J Neurol Sci 119:195–202PubMedGoogle Scholar
  77. 77.
    Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, Murray BM, Barres B, Tessier-Levigne M, Bernard CC (2004) The neurite out-growth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nature Neurosci 7:736–744PubMedGoogle Scholar
  78. 78.
    Kassiotis G, Kollias G (2001) Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: Implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 193:427–434PubMedGoogle Scholar
  79. 79.
    Kawaja MD, Gage FH (1991) Reactive astrocytes are substarte for the growth of adult CNS axons in the presence of elevated levels of nerve growth factors. Neuron 7:1019–1030PubMedGoogle Scholar
  80. 80.
    Kerschensteiner M, Gallmeier E, Behrens L, Vargas Leal V, Misgeld T, Klinkert WEF, Kolbeck R, Hoppe E, Oropeza-Wekerle R, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells and monocytes produced brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: A neuroprotective role of inflammation? J Exp Med 189:865–870CrossRefPubMedGoogle Scholar
  81. 81.
    Kerschensteiner M, Stadelmann C, Dechant G, Wekerle H, Hohlfeld R (2003) Neurotrophic cross-talk between the nervous and immune systems: Implications for neurological diseases. Ann Neurol 53:292–304CrossRefPubMedGoogle Scholar
  82. 82.
    Kiefer R, Funa K, Schweitzer T, Jung S, Bourde O, Toyka KV, Hartung HP (1996) Transforming growth factor-β1 in experimental autoimmune neuritis: cellular localization and time course. Am J Pathol 148:211–223PubMedGoogle Scholar
  83. 83.
    Koski CL (1998) Immune interactions in the peripheral nervous system. In: Latov N, Wokke JHJ, Kelly JJ Jr (eds). Immunology and infectious diseases of the peripheral nerves. Cambridge University Press, Cambridge, pp 1–28Google Scholar
  84. 84.
    Kotter MR, Setzu A, Sim FJ, Van Rooijen N, Franklin RJM (2001) Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 35:204–212PubMedGoogle Scholar
  85. 85.
    Krakowski M, Owens T (1996) Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol 26:1641–1646PubMedGoogle Scholar
  86. 86.
    Kuhlmann T, Bruck W (1999) Immunoglobulins induced myelin debris clearance by mouse macrophages. Neurosci Lett 19:191–194Google Scholar
  87. 87.
    Lambiase A, Bracci-Laudiero L, Bonini S, Bonini S, Starace G, D’Elios MM, De Carli M, Aloe L (1997) Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors. J Allergy Clin Immunol 100:408–414PubMedGoogle Scholar
  88. 88.
    Latov N, Wokke JHJ, Kelly JJ Jr (1998) Immunology and infectious diseases of the peripheral nerves. Cambridge University Press, CambridgeGoogle Scholar
  89. 89.
    Lazarov-Spiegeler O, Salomon AS, Zeev-Brann AB, Hirschberg DL, Lavie V, Schwartz M (1996) Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J 10:1296–1302PubMedGoogle Scholar
  90. 90.
    Lazarov-Spiegeler O, Salomon AS, Schwartz M (1998) Peripheral nervestimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optic nerve. Glia 24:329–337PubMedGoogle Scholar
  91. 91.
    Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317CrossRefPubMedGoogle Scholar
  92. 92.
    Lilje O, Armati PJ (1997) The distribution and abundance of MHC and ICAM-1 on Schwann cells in vitro. J Neuroimmunol 77:75–84PubMedGoogle Scholar
  93. 93.
    Lindholm D, Heumann R, Meyer M, Thoenen H (1987) Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 330:658–659PubMedGoogle Scholar
  94. 94.
    Linker RA, Mäurer M, Gaupp S, Martini R, Holtmann B, Giess R, Rieckmann P, Lassman H, Toyka KV, Sendtner M, Gold R (2002) CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation. Nature Med 8:620–624PubMedGoogle Scholar
  95. 95.
    Lisak RP, Bealmer B, Ragheb S (1994) Interleukin-1 alpha, but not interleukin 1-beta, is a co-mitogen for neonatal rat Schwann cells in vitro and acts via interleukin-1 receptors. J Neuroimmunol 55:171–177PubMedGoogle Scholar
  96. 96.
    Mancardi GL, Cadoni A, Zicca A, Schenone A, Tabaton A, De Martin A, Zaccheo D (1988) HLA-DR Schwann cell reactivity in peripheral neuropathies of different origins. Neurology 38:848–851PubMedGoogle Scholar
  97. 97.
    Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis E, Yoshimura A, Ihle JN (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609–616PubMedGoogle Scholar
  98. 98.
    Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10:153–187PubMedGoogle Scholar
  99. 99.
    Massa PT, ter Meulen V, Fontana A (1987) Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 84:4219–4223PubMedGoogle Scholar
  100. 100.
    Masson JL, Jones JJ, Taniike M, Morelll P, Suzuki K, Matsushima GK (2000) Mature oligodendrocytes apoptosis precedes IGF-I production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination. J Neurosci Res 61:251–262PubMedGoogle Scholar
  101. 101.
    Masson JL, Suzuki K, Chaplin DD, Matsushima GK (2001) Interleukin-1β promotes repair of the CNS. J Neurosci 21:7046–7052PubMedGoogle Scholar
  102. 102.
    Matsumoto Y, Ohmori K, Fujiwara M (1992) Immune regulation by brain cells in the central nervous system by microglia but not astrocytes present myelin basic protein to encephalitogenic T cells under in vivo-mimicking conditions (1992). Immunology 76:209–216PubMedGoogle Scholar
  103. 103.
    Mears S, Schachner M, Brushart TM (2003) Antibodies to myelin-associated glycoprotein accelerate preferential motor reinnervation. J Peripher Nerv Syst 8:91–99PubMedGoogle Scholar
  104. 104.
    Melamed I, Kelleher CA, Franklin RA, Brodie C, Hempstead B, Kaplan D, Gelfand EW (1996) Nerve growth signal transduction in human B lymphocytes is mediated by gp 140trk. Eur J Immunol 26:1985–1992PubMedGoogle Scholar
  105. 105.
    Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M (1999) Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nature Med 5:49–55PubMedGoogle Scholar
  106. 106.
    Mohan R, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, Richert JR, Siegel JN (2001) Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritis. Arthritis Rheum 44:2862–2869PubMedGoogle Scholar
  107. 107.
    Mukhopadhyay G, Doherty P, Walsh FS, Crocker PR, Filbin MT (1994) A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13:757–767PubMedGoogle Scholar
  108. 108.
    Neumann H, Misgeld T, Matsumuro K, Wekerle H (1998) Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. Proc Natl Acad Sci 95:5779–5784CrossRefPubMedGoogle Scholar
  109. 109.
    Otten U, Ehrhard P, Peck E (1989) Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci 86:10059–10063PubMedGoogle Scholar
  110. 110.
    Ousman SS, David S (2000) Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia 30:92–104PubMedGoogle Scholar
  111. 111.
    Oya T, Zhao YL, Takagawa K, Kawaguchi M, Shirakawa K,Yamauchi T, Sasahara M (2002) Platelet-derived growth factor-β expression induced after rat peripheral nerve injuries. Glia 38:303–312PubMedGoogle Scholar
  112. 112.
    Pachter JS, de Vries HE, Fabry Z (2003) The blood-brain barrier and its role in immune privilege in the Central Nervous System. J Neuropathol Exp Neurol 62:593–604Google Scholar
  113. 113.
    Panitch HS, Hirsch RL, Schindler J, Johnson KP (1987) Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37:1097–1102PubMedGoogle Scholar
  114. 114.
    Paz Soldan MM, Warrington AE, Bieber AJ, Ciric B, Van Keulen V, Pease LR, Rodríguez M (2003) Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanisms of myelin repair. Moll Cell Neurosci 22:14–24Google Scholar
  115. 115.
    Perry VH, Brown MC, Gordon S (1987) The macrophage response to central and peripheral injury: A possible role for macrophages in regeneration. J Exp Med 165:1218–1223PubMedGoogle Scholar
  116. 116.
    Pollard JD, Baverstocl J, McLeod JG (1987) Class II antigen expression and inflammatory cells in the Guillain-Barré syndrome. Ann Neurol 21:337–341PubMedGoogle Scholar
  117. 117.
    Poulsen FR, Lagord C, Courty J, Pedersen EB, Barritault D, Finsen B (2000) Increased synthesis of heparin affin regulatory peptide in the perforant path lesioned mouse hippocampal formation. Exp Brain Res 135:319–330PubMedGoogle Scholar
  118. 118.
    Prineas JW, McLeod JG (1976) Chronic relapsing polyneuritis. J Neurol Sci 27:427–458PubMedGoogle Scholar
  119. 119.
    Prineas JW (1981) Pathology of Guillain-Barre syndrome. Ann Neurol 9(Suppl):6–19PubMedGoogle Scholar
  120. 120.
    Rabchensky AG, Streitt WJ (1997) Grafting of cultured microglia cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res 47:34–48PubMedGoogle Scholar
  121. 121.
    Ransohoff RR, Benveniste EN (1996) Cytokines and the CNS. CRC Press, Boca RatonGoogle Scholar
  122. 122.
    Ransohoff RM, Howe CL, Rodriguez M (2002) Growth factor treatment of demyelinating disease: at last, a leap into the light. Trends Immunol 23:512–516PubMedGoogle Scholar
  123. 123.
    Rapalino O, Lazarov-Spiegeler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nature Med 4:814–821PubMedGoogle Scholar
  124. 124.
    Reichert F, Levitzky R, Rothshenker S (1996) Interleukin 6 in intact and injured mouse peripheral nerves. Eur J Neurosci 8:530–535PubMedGoogle Scholar
  125. 125.
    Robinson S, Miller RH (1999) Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev Biol 216:359–368PubMedGoogle Scholar
  126. 126.
    Rodriguez M, Lennon VA, Benveniste EN, Merril JE (1987) Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol 46:84–95PubMedGoogle Scholar
  127. 127.
    Rotshenker S, Aamar S, Barak V (1992) Interleukin-1 activity in lesioned peripheral nerve. J Neuroimmunol 39:75–80PubMedGoogle Scholar
  128. 128.
    Saada A, Reichert F, Rotshenker S (1996) Granulocyte macrophage colony stimulating factor produced in lesioned peripheral nerves induces the up-regulation of cell surface expression of MAC-2 by macrophages and Schwann cells. J Cell Biol 133:159–167PubMedGoogle Scholar
  129. 129.
    Santambrogio L, Benedetti M, Caho MV, Muzaffar R, Kulig K, Gabell N, Hochwald G (1994) Nerve growth factor production by lymphocytes. J Immunol 153:4488–4495PubMedGoogle Scholar
  130. 130.
    Scherbel U, Raghupathi R, Nakamura M, Saatman KE, Trojanowski JQ, Neugebauer E,Marino MW, McIntosh TK (1999) Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci 96:8721–8726PubMedGoogle Scholar
  131. 131.
    Schmidt B, Stoll G,Hartung HP, Heininger K, Schafer B, Toyka KV (1990) Macrophages but not Schwann cells express Ia antigen in experimental allergic neuritis. Ann Neurol 28:70–77PubMedGoogle Scholar
  132. 132.
    Schwartz M, Hauben E (2002) T-cell based therapeutic vaccination for spinal cord injury. Prog Brain Res 137:401–406PubMedGoogle Scholar
  133. 133.
    Sedgwick JD, Mossner R, Schwender S, ter Meulen V (1991) Major histocompatibility complex-expressing nonhematopoietic astroglial cells prime only CD8+ T lymphocytes: astroglial cells as perpetuators but not initiators of CD4+ T cell responses in the central nervous system. J Exp Med 173:1235–1246PubMedGoogle Scholar
  134. 134.
    Shamash S, Reichert F, Rotshenker S (2002) The Cytokine network of Wallerian degeneration: Tumor necrosis factor-α, and Interleukin-1β. J Neurosci 22:3052–3060PubMedGoogle Scholar
  135. 135.
    Shields SA, Gilson JM, Blakemore WF, Franklin RJM (1999) Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 28:77–83PubMedGoogle Scholar
  136. 136.
    Sicotte NL, Voskhul RR (2001) Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 57:1885–1888PubMedGoogle Scholar
  137. 137.
    Sindern E, Schweppe K, Ossege LM, Mailin JP (1996) Potential role of transforming growth factor-β1 in terminating the immune response in patients with Guillain-Barré syndrome. J Neurol 243:264–268PubMedGoogle Scholar
  138. 138.
    Sobue G, Yamamoto M, Doyu M, Li M, Yasuda T, Mitsuma T (1998) Expression of mRNA for neurotrophins (NGF, BDNF, and NT-3) and their receptors (p75NGFR, trkB, and trkC) in human peripheral neuropathies. Neurochem Res 23:821–829PubMedGoogle Scholar
  139. 139.
    Stadelmann C, Kerschensteiner M, Misgeld T, Brück W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125:75–85CrossRefPubMedGoogle Scholar
  140. 140.
    Stoll G, Griffin JW, Li CY, Trapp BD (1989) Wallerian degeneration in the peripheral nervous system: Participation of both Schwann cells and macrophages in myelin degradation. J Neurocytol 18:671–683PubMedGoogle Scholar
  141. 141.
    Stoll G, Jung S, Van der Meide P, Hartung HP (1993) Tumor necrosis factor-alpha in immune mediated demyelination and Wallerian degeneration of the peripheral nervous system. J Neuroimmunol 45:175–182PubMedGoogle Scholar
  142. 142.
    The Lenercep Group (1999) TNF neutralization in MS: results of a randomized placebo-controlled multicenter study. Neurology 53:457–465PubMedGoogle Scholar
  143. 143.
    Thorpe LW, Perez-Polo JR (1987) The influence of nerve growth factor on in vitro proliferative response of rat spleen lymphocytes. J Neurosci Res 18:134–139PubMedGoogle Scholar
  144. 144.
    Torcia M, Bracci-Laudiero L, Lucibello M, Nencioni L, Labardi D, Rubartelli A, Cozzolino F, Aloe L, Garaci E (1996) Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 85:345–356PubMedGoogle Scholar
  145. 145.
    van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH (1996) Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47:1531–1534PubMedGoogle Scholar
  146. 146.
    Villoslada P,Hauser SL, Bartke I, Unger J, Heald N, Rosenberg D, Cheung SW, Mobley WC, Fisher S, Genain CP (2000) Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 191:1799–1806PubMedGoogle Scholar
  147. 147.
    Wagner R, Myers RR (1996) Schwann cells produce tumor necrosis factor alpha: expression in injured and non-injured nerves. Neuroscience 73:625–629PubMedGoogle Scholar
  148. 148.
    Warrington AE, Asakura K, Bieber AJ, Ciric B, Van Keulen V, Kaveri SV, Kyle RA, Pease LR, Rodriguez M (2000) Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci 97:6820–6825PubMedGoogle Scholar
  149. 149.
    Warrington AE, Bieber AJ, van Keulen V, Ciric B, Pease LR, Rodriguez M (2004) Neuron-binding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol 63:461–473PubMedGoogle Scholar
  150. 150.
    Weber F, Meinl E, Aloisi F, Nevinny-Stickel C, Albert E, Wekerle H, Hohlfeld R (1994) Human astrocytes are only partially competent antigen presenting cells. Possible implications for lesion development in multiple sclerosis. Brain 117:59–69PubMedGoogle Scholar
  151. 151.
    Wei R, Jonakait GM (1999) Neurotrophins and the anti-inflammatory agents interleukin-4 (IL-4), IL-10, IL-11 and transforming growth factor beta-1 (TGF-beta 1) down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat microglia. J Neuroimmunol 95:8–18PubMedGoogle Scholar
  152. 152.
    Weishaupt A, Gold R, Hartung H, Gaupp S, Brück W, Toyka KV (2000) Role of TNF-α in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-α by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis. J Neuropathol Exp Neurol 59:368–376PubMedGoogle Scholar
  153. 153.
    Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA (1996) IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 157:3223–3227PubMedGoogle Scholar
  154. 154.
    Williams K, Ulvestad E, Antel JP (1994) B7/BB-1 antigen expression on adult microglia studied in vitro and in situ. Eur J Immunol 24:3031–3037PubMedGoogle Scholar
  155. 155.
    Windhangen A, Newcombe J, Dangond F, Strand C, Woodroofe MNB, Cuzner ML, Hafler DA (1995) Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 182:1985–1996PubMedGoogle Scholar
  156. 156.
    Woodruff RH, Franklin RJM (1999) The expression of myelin protein mRNAs during remyelination of lysolecithin-induced demyelination. Neuropathol Appl Neurobiol 25:226–235PubMedGoogle Scholar
  157. 157.
    Yamamoto M, Sobue G, Li M, Arakawa Y, Mitsuma T, Kimata K (1993) Nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and low-affinity nerve growth factor receptor (LNGFR) mRNA levels in cultured rat Schwann cells; differential time-and-dose-dependent regulation by cAMP. Neurosci Lett 152:37–40PubMedGoogle Scholar
  158. 158.
    Yao DL, Liu X, Hudson LD, Webster HD (1995) Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 92:6190–6194PubMedGoogle Scholar
  159. 159.
    Yoles E, Hauben E, Palgi O, Agarnov E, Gothilf A, Cohen A, Kuchroo V, Cohen IR, Weiner HL, Schwartz M (2001) Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 21:3740–3748PubMedGoogle Scholar
  160. 160.
    Zeev-Brann AB, Lazarov-Spiegler O, Brenner T, Schwartz M (1998) Differential effects of central and peripheral nerves on macrophages and microglia. Glia 23:181–190PubMedGoogle Scholar
  161. 161.
    Zettl UK, Mix E, Zielasek J, Stangel M, Hartung HP, Gold R (1997) Apoptosis of myelin-reactive T cells induced by reactive oxygen and nitrogen intermediates in vitro. Cell Immunol 178:1–8PubMedGoogle Scholar

Copyright information

© Steinkopff Verlag 2004

Authors and Affiliations

  1. 1.Raúl Carrea Institute for Neurological Research, FLENIBuenos AiresArgentina
  2. 2.School of Biological SciencesAustral UniversityPilar Buenos AiresArgentina
  3. 3.Dept. of NeurologyJosé María Ramos Mejía Hospital, School of Medicine, Buenos Aires UniversityBuenos AiresArgentina

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