Journal of Molecular Medicine

, Volume 86, Issue 9, pp 975–985

New developments in understanding and treating neuroinflammation

  • C. Infante-Duarte
  • S. Waiczies
  • J. Wuerfel
  • F. Zipp


We are currently witnesses to and authors of a paradigm shift in neuropathology. While classical acute and chronic neuroinflammatory diseases such as meningitis or multiple sclerosis (MS) present aspects of neurodegeneration, the disease course of progressive degenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), or stroke-mediated neuronal deficit are demonstrably affected by inflammation. These insights have immediate consequences both for research methods and for the development of novel, more efficient therapies for these diseases. In this review, we analyze the inflammatory and degenerative pathological mechanisms in the brain with particular emphasis on the classical chronic inflammatory disease MS. We demonstrate that the latest pathological considerations not only require the application of advanced research technologies to investigate new pathomechanistic pathways, but also affect the investigation, development, and monitoring of novel potential therapeutic tools.


Multiple sclerosis Neuroinflammation Neurodegeneration T cell 


  1. 1.
    Zipp F, Aktas O (2006) The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 29:518–527PubMedCrossRefGoogle Scholar
  2. 2.
    Hickey WF (1991) Migration of hematogenous cells through the blood–brain barrier and the initiation of CNS inflammation. Brain Pathol 1:97–105PubMedCrossRefGoogle Scholar
  3. 3.
    McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200PubMedCrossRefGoogle Scholar
  4. 4.
    Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9:339–349PubMedCrossRefGoogle Scholar
  5. 5.
    McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291PubMedGoogle Scholar
  6. 6.
    Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605PubMedCrossRefGoogle Scholar
  7. 7.
    Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol (Berl) 106:518–526CrossRefGoogle Scholar
  8. 8.
    McGeer PL, Rogers J, McGeer EG (2006) Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis 9:271–276PubMedGoogle Scholar
  9. 9.
    Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A (2005) Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann Neurol 58:963–967PubMedCrossRefGoogle Scholar
  10. 10.
    Chen H, Zhang SM, Hernan MA, Schwarzschild MA, Willett WC, Colditz GA, Speizer FE, Ascherio A (2003) Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 60:1059–1064PubMedCrossRefGoogle Scholar
  11. 11.
    Hancock DB, Martin ER, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance JM, Scott WK (2007) Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson disease. Arch Neurol 64:576–580PubMedCrossRefGoogle Scholar
  12. 12.
    Group AR, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, Piantadosi S, Sabbagh M (2007) Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 68:1800–1808CrossRefGoogle Scholar
  13. 13.
    Hernan MA, Logroscino G, Garcia Rodriguez LA (2006) Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease. Neurology 66:1097–1099PubMedCrossRefGoogle Scholar
  14. 14.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69PubMedCrossRefGoogle Scholar
  15. 15.
    Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, Prass K, Meisel A (2007) Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke 38:770–773PubMedCrossRefGoogle Scholar
  16. 16.
    Weber JR, Tuomanen EI (2007) Cellular damage in bacterial meningitis: an interplay of bacterial and host driven toxicity. J Neuroimmunol 184:45–52PubMedCrossRefGoogle Scholar
  17. 17.
    Hoffmann O, Priller J, Prozorovski T, Schulze-Topphoff U, Baeva N, Lunemann JD, Aktas O, Mahrhofer C, Stricker S, Zipp F, Weber JR (2007) TRAIL limits excessive host immune response in bacterial meningitis. J Clin Invest 117:2004–2013PubMedCrossRefGoogle Scholar
  18. 18.
    Aktas O, Ullrich O, Infante-Duarte C, Nitsch R, Zipp F (2007) Neuronal damage in brain inflammation. Arch Neurol 64:185–189PubMedCrossRefGoogle Scholar
  19. 19.
    Aktas O, Waiczies S, Zipp F (2007) Neurodegeneration in autoimmune demyelination: recent mechanistic insights reveal novel therapeutic targets. J Neuroimmunol 184:17–26PubMedCrossRefGoogle Scholar
  20. 20.
    Hickey WF (2001) Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118–124PubMedCrossRefGoogle Scholar
  21. 21.
    Brabb T, von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J (2000) In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J Exp Med 192:871–880PubMedCrossRefGoogle Scholar
  22. 22.
    Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292PubMedCrossRefGoogle Scholar
  23. 23.
    Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 84:532–543PubMedCrossRefGoogle Scholar
  24. 24.
    Kermode AG, Thompson AJ, Tofts P, MacManus DG, Kendall BE, Kingsley DP, Moseley IF, Rudge P, McDonald WI (1990) Breakdown of the blood–brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 113(Pt 5):1477–1489PubMedCrossRefGoogle Scholar
  25. 25.
    Nitsch R, Pohl EE, Smorodchenko A, Infante-Duarte C, Aktas O, Zipp F (2004) Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. J Neurosci 24:2458–2464PubMedCrossRefGoogle Scholar
  26. 26.
    Kawakami N, Nagerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flugel A (2005) Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J Exp Med 201:1805–1814PubMedCrossRefGoogle Scholar
  27. 27.
    Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, Ebers GC (2006) Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 5:932–936PubMedCrossRefGoogle Scholar
  28. 28.
    Kantarci O, Wingerchuk D (2006) Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol 19:248–254PubMedCrossRefGoogle Scholar
  29. 29.
    Marrie RA (2004) Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 3:709–718PubMedCrossRefGoogle Scholar
  30. 30.
    Giovannoni G, Cutter GR, Lunemann J, Martin R, Munz C, Sriram S, Steiner I, Hammerschlag MR, Gaydos CA (2006) Infectious causes of multiple sclerosis. Lancet Neurol 5:887–894PubMedCrossRefGoogle Scholar
  31. 31.
    Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747PubMedCrossRefGoogle Scholar
  32. 32.
    Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 8:579–621PubMedCrossRefGoogle Scholar
  33. 33.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240PubMedCrossRefGoogle Scholar
  34. 34.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133PubMedCrossRefGoogle Scholar
  35. 35.
    Hofstetter HH, Toyka KV, Tary-Lehmann M, Lehmann PV (2007) Kinetics and organ distribution of IL-17-producing CD4 cells in proteolipid protein 139–151 peptide-induced experimental autoimmune encephalomyelitis of SJL mice. J Immunol 178:1372–1378PubMedGoogle Scholar
  36. 36.
    Nyland H, Mork S, Matre R (1982) In-situ characterization of mononuclear cell infiltrates in lesions of multiple sclerosis. Neuropathol Appl Neurobiol 8:403–411PubMedCrossRefGoogle Scholar
  37. 37.
    Traugott U, Reinherz EL, Raine CS (1983) Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science 219:308–310PubMedCrossRefGoogle Scholar
  38. 38.
    Hauser SL, Bhan AK, Gilles F, Kemp M, Kerr C, Weiner HL (1986) Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol 19:578–587PubMedCrossRefGoogle Scholar
  39. 39.
    Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508PubMedCrossRefGoogle Scholar
  40. 40.
    Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, McFarland HF, Martin R (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175PubMedCrossRefGoogle Scholar
  41. 41.
    Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23PubMedCrossRefGoogle Scholar
  42. 42.
    Balcer LJ, Galetta SL, Calabresi PA, Confavreux C, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Miller DH, O’Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA (2007) Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology 68:1299–1304PubMedCrossRefGoogle Scholar
  43. 43.
    Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910PubMedCrossRefGoogle Scholar
  44. 44.
    Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124–1140PubMedCrossRefGoogle Scholar
  45. 45.
    O’Connor P (2002) Key issues in the diagnosis and treatment of multiple sclerosis. An overview. Neurology 59:S1–33PubMedGoogle Scholar
  46. 46.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3):393–399PubMedCrossRefGoogle Scholar
  47. 47.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285PubMedCrossRefGoogle Scholar
  48. 48.
    Coles AJ, Wing MG, Molyneux P, Paolillo A, Davie CM, Hale G, Miller D, Waldmann H, Compston A (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296–304PubMedCrossRefGoogle Scholar
  49. 49.
    Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276PubMedGoogle Scholar
  50. 50.
    Evangelou N, Esiri MM, Smith S, Palace J, Matthews PM (2000) Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 47:391–395PubMedCrossRefGoogle Scholar
  51. 51.
    Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212PubMedCrossRefGoogle Scholar
  52. 52.
    Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T (1999) Cortical lesions in multiple sclerosis. Brain 122(Pt 1):17–26PubMedCrossRefGoogle Scholar
  53. 53.
    Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400PubMedCrossRefGoogle Scholar
  54. 54.
    Sailer M, Fischl B, Salat D, Tempelmann C, Schonfeld MA, Busa E, Bodammer N, Heinze HJ, Dale A (2003) Focal thinning of the cerebral cortex in multiple sclerosis. Brain 126:1734–1744PubMedCrossRefGoogle Scholar
  55. 55.
    Mathiesen HK, Jonsson A, Tscherning T, Hanson LG, Andresen J, Blinkenberg M, Paulson OB, Sorensen PS (2006) Correlation of global N-acetyl aspartate with cognitive impairment in multiple sclerosis. Arch Neurol 63:533–536PubMedCrossRefGoogle Scholar
  56. 56.
    Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P (2005) Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol 64:1101–1107PubMedCrossRefGoogle Scholar
  57. 57.
    Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM (2000) Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123(Pt 9):1845–1849PubMedCrossRefGoogle Scholar
  58. 58.
    Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123(Pt 6):1174–1183PubMedCrossRefGoogle Scholar
  59. 59.
    DeLuca GC, Williams K, Evangelou N, Ebers GC, Esiri MM (2006) The contribution of demyelination to axonal loss in multiple sclerosis. Brain 129:1507–1516PubMedCrossRefGoogle Scholar
  60. 60.
    Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, Nave KA (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613PubMedCrossRefGoogle Scholar
  61. 61.
    Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1:232–241PubMedCrossRefGoogle Scholar
  62. 62.
    Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489PubMedCrossRefGoogle Scholar
  63. 63.
    Inglese M, Ge Y, Filippi M, Falini A, Grossman RI, Gonen O (2004) Indirect evidence for early widespread gray matter involvement in relapsing–remitting multiple sclerosis. Neuroimage 21:1825–1829PubMedCrossRefGoogle Scholar
  64. 64.
    Giuliani F, Yong VW (2003) Immune-mediated neurodegeneration and neuroprotection in MS. Int MS J 10:122–130PubMedGoogle Scholar
  65. 65.
    Smorodchenko A, Wuerfel J, Pohl EE, Vogt J, Tysiak E, Glumm R, Hendrix S, Nitsch R, Zipp F, Infante-Duarte C (2007) CNS-irrelevant T-cells enter the brain, cause blood–brain barrier disruption but no glial pathology. Eur J Neurosci 26:1387–1398PubMedCrossRefGoogle Scholar
  66. 66.
    Minagar A, Alexander JS (2003) Blood–brain barrier disruption in multiple sclerosis. Mult Scler 9:540–549PubMedCrossRefGoogle Scholar
  67. 67.
    Aktas O, Smorodchenko A, Brocke S, Infante-Duarte C, Topphoff US, Vogt J, Prozorovski T, Meier S, Osmanova V, Pohl E, Bechmann I, Nitsch R, Zipp F (2005) Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46:421–432PubMedCrossRefGoogle Scholar
  68. 68.
    Neumann H, Medana IM, Bauer J, Lassmann H (2002) Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 25:313–319PubMedCrossRefGoogle Scholar
  69. 69.
    Diestel A, Aktas O, Hackel D, Hake I, Meier S, Raine CS, Nitsch R, Zipp F, Ullrich O (2003) Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med 198:1729–1740PubMedCrossRefGoogle Scholar
  70. 70.
    Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, Schenkel J, Herdegen T, Debatin KM (1999) CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci 19:3809–3817PubMedGoogle Scholar
  71. 71.
    Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5:629–640PubMedCrossRefGoogle Scholar
  72. 72.
    Moncada S, Bolanos JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97:1676–1689PubMedCrossRefGoogle Scholar
  73. 73.
    Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505PubMedCrossRefGoogle Scholar
  74. 74.
    Hartung HP, Bar-Or A, Zoukos Y (2004) What do we know about the mechanism of action of disease-modifying treatments in MS? J Neurol 251(Suppl 5):v12–v29PubMedCrossRefGoogle Scholar
  75. 75.
    Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453–21457PubMedCrossRefGoogle Scholar
  76. 76.
    Massberg S, von Andrian UH (2006) Fingolimod and sphingosine-1-phosphate-modifiers of lymphocyte migration. N Engl J Med 355:1088–1091PubMedCrossRefGoogle Scholar
  77. 77.
    Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, English D (2001) Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 108:689–701PubMedCrossRefGoogle Scholar
  78. 78.
    Jaillard C, Harrison S, Stankoff B, Aigrot MS, Calver AR, Duddy G, Walsh FS, Pangalos MN, Arimura N, Kaibuchi K, Zalc B, Lubetzki C (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 25:1459–1469PubMedCrossRefGoogle Scholar
  79. 79.
    Novgorodov AS, El-Alwani M, Bielawski J, Obeid LM, Gudz TI (2007) Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J 21:1503–1514PubMedCrossRefGoogle Scholar
  80. 80.
    Ishii I, Fukushima N, Ye X, Chun J (2004) Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 73:321–354PubMedCrossRefGoogle Scholar
  81. 81.
    Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354:911–923PubMedCrossRefGoogle Scholar
  82. 82.
    Miller DH, Soon D, Fernando KT, MacManus DG, Barker GJ, Yousry TA, Fisher E, O’Connor PW, Phillips JT, Polman CH, Kappos L, Hutchinson M, Havrdova E, Lublin FD, Giovannoni G, Wajgt A, Rudick R, Lynn F, Panzara MA, Sandrock AW (2007) MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68:1390–1401PubMedCrossRefGoogle Scholar
  83. 83.
    Paolillo A, Coles AJ, Molyneux PD, Gawne-Cain M, MacManus D, Barker GJ, Compston DA, Miller DH (1999) Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology 53:751–757PubMedGoogle Scholar
  84. 84.
    Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, Weetman A, Hale G, Chatterjee VK, Waldmann H, Compston A (1999) Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354:1691–1695PubMedCrossRefGoogle Scholar
  85. 85.
    Coles A, Deans J, Compston A (2004) Campath-1H treatment of multiple sclerosis: lessons from the bedside for the bench. Clin Neurol Neurosurg 106:270–274PubMedCrossRefGoogle Scholar
  86. 86.
    Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62:258–264PubMedCrossRefGoogle Scholar
  87. 87.
    Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C (2005) An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64:1270–1272PubMedGoogle Scholar
  88. 88.
    Paul F, Jarius S, Aktas O, Bluthner M, Bauer O, Appelhans H, Franciotta D, Bergamaschi R, Littleton E, Palace J, Seelig HP, Hohlfeld R, Vincent A, Zipp F (2007) Antibody to aquaporin 4 in the diagnosis of neuromyelitis optica. PLoS Med 4:e133PubMedCrossRefGoogle Scholar
  89. 89.
    Langer-Gould A, Steinman L (2006) What went wrong in the natalizumab trials? Lancet 367:708–710PubMedCrossRefGoogle Scholar
  90. 90.
    Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA (2006) The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 253:98–108PubMedCrossRefGoogle Scholar
  91. 91.
    Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, O’Connor PW, King J, Radue EW, Yousry T, Major EO, Clifford DB (2007) Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 6:431–441PubMedCrossRefGoogle Scholar
  92. 92.
    Zipp F, Hartung HP, Hillert J, Schimrigk S, Trebst C, Stangel M, Infante-Duarte C, Jakobs P, Wolf C, Sandbrink R, Pohl C, Filippi M (2006) Blockade of chemokine signaling in patients with multiple sclerosis. Neurology 67:1880–1883PubMedCrossRefGoogle Scholar
  93. 93.
    Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, Hancock WW (2000) Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol 30:2372–2377PubMedCrossRefGoogle Scholar
  94. 94.
    Liang M, Mallari C, Rosser M, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B, Shaw K, Wei GP, Xu W, Zhao Z, Ho E, Shen J, Oanh H, Subramanyam B, Vergona R, Taub D, Dunning L, Harvey S, Snider RM, Hesselgesser J, Morrissey MM, Perez HD (2000) Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 275:19000–19008PubMedCrossRefGoogle Scholar
  95. 95.
    Eltayeb S, Sunnemark D, Berg AL, Nordvall G, Malmberg A, Lassmann H, Wallstrom E, Olsson T, Ericsson-Dahlstrand A (2003) Effector stage CC chemokine receptor-1 selective antagonism reduces multiple sclerosis-like rat disease. J Neuroimmunol 142:75–85PubMedCrossRefGoogle Scholar
  96. 96.
    Frantz S (2005) Drug discovery: playing dirty. Nature 437:942–943PubMedCrossRefGoogle Scholar
  97. 97.
    Matsunaga K, Klein TW, Friedman H, Yamamoto Y (2001) Legionella pneumophila replication in macrophages inhibited by selective immunomodulatory effects on cytokine formation by epigallocatechin gallate, a major form of tea catechins. Infect Immun 69:3947–3953PubMedCrossRefGoogle Scholar
  98. 98.
    Mukhtar H, Ahmad N (1999) Green tea in chemoprevention of cancer. Toxicol Sci 52:111–117PubMedGoogle Scholar
  99. 99.
    Suganuma M, Okabe S, Sueoka N, Sueoka E, Matsuyama S, Imai K, Nakachi K, Fujiki H (1999) Green tea and cancer chemoprevention. Mutat Res 428:339–344PubMedGoogle Scholar
  100. 100.
    Chung FL, Schwartz J, Herzog CR, Yang YM (2003) Tea and cancer prevention: studies in animals and humans. J Nutr 133:3268S–3274SPubMedGoogle Scholar
  101. 101.
    Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H (1997) Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 89:1881–1886PubMedCrossRefGoogle Scholar
  102. 102.
    Yang GY, Liao J, Kim K, Yurkow EJ, Yang CS (1998) Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Carcinogenesis 19:611–616PubMedCrossRefGoogle Scholar
  103. 103.
    Liang YC, Lin-Shiau SY, Chen CF, Lin JK (1999) Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (−)-epigallocatechin-3-gallate. J Cell Biochem 75:1–12PubMedCrossRefGoogle Scholar
  104. 104.
    Lu YP, Lou YR, Xie JG, Peng QY, Liao J, Yang CS, Huang MT, Conney AH (2002) Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. Proc Natl Acad Sci USA 99:12455–12460PubMedCrossRefGoogle Scholar
  105. 105.
    Hsu S, Bollag WB, Lewis J, Huang Q, Singh B, Sharawy M, Yamamoto T, Schuster G (2003) Green tea polyphenols induce differentiation and proliferation in epidermal keratinocytes. J Pharmacol Exp Ther 306:29–34PubMedCrossRefGoogle Scholar
  106. 106.
    Yamamoto T, Hsu S, Lewis J, Wataha J, Dickinson D, Singh B, Bollag WB, Lockwood P, Ueta E, Osaki T, Schuster G (2003) Green tea polyphenol causes differential oxidative environments in tumor versus normal epithelial cells. J Pharmacol Exp Ther 307:230–236PubMedCrossRefGoogle Scholar
  107. 107.
    Haqqi TM, Anthony DD, Gupta S, Ahmad N, Lee MS, Kumar GK, Mukhtar H (1999) Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea. Proc Natl Acad Sci USA 96:4524–4529PubMedCrossRefGoogle Scholar
  108. 108.
    Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel PM, Infante-Duarte C, Brocke S, Zipp F (2004) Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 173:5794–5800PubMedGoogle Scholar
  109. 109.
    Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S (2001) Green tea polyphenol (−)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 78:1073–1082PubMedCrossRefGoogle Scholar
  110. 110.
    Choi JY, Park CS, Kim DJ, Cho MH, Jin BK, Pie JE, Chung WG (2002) Prevention of nitric oxide-mediated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease in mice by tea phenolic epigallocatechin 3-gallate. Neurotoxicology 23:367–374PubMedCrossRefGoogle Scholar
  111. 111.
    Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25:8807–8814PubMedCrossRefGoogle Scholar
  112. 112.
    Lee S, Suh S, Kim S (2000) Protective effects of the green tea polyphenol (−)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 287:191–194PubMedCrossRefGoogle Scholar
  113. 113.
    Hendriks JJ, Alblas J, van der Pol SM, van Tol EA, Dijkstra CD, de Vries HE (2004) Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med 200:1667–1672PubMedCrossRefGoogle Scholar
  114. 114.
    Waiczies S, Prozorovski T, Zipp F (2005) Modulating T cell signaling cascades by HMG-CoA reductase inhibitors. Signal Transduct 5:231–244CrossRefGoogle Scholar
  115. 115.
    Zipp F, Waiczies S, Aktas O, Neuhaus O, Hemmer B, Schraven B, Nitsch R, Hartung H-P (2007) Impact of HMG-CoA reductase inhibition on brain pathology. Trends Pharmacol Sci 28:342–349PubMedCrossRefGoogle Scholar
  116. 116.
    Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, Prozorovski T, Sallach S, Endres M, Brocke S, Nitsch R, Zipp F (2003) Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 197:725–733PubMedCrossRefGoogle Scholar
  117. 117.
    Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84PubMedCrossRefGoogle Scholar
  118. 118.
    Waiczies S, Prozorovski T, Infante-Duarte C, Hahner A, Aktas O, Ullrich O, Zipp F (2005) Atorvastatin induces T cell anergy via phosphorylation of ERK1. J Immunol 174:5630–5635PubMedGoogle Scholar
  119. 119.
    Waiczies S, Bendix I, Prozorovski T, Ratner M, Nazarenko I, Pfueller CF, Brandt AU, Herz J, Brocke S, Ullrich O, Zipp F (2007) Geranylgeranylation but not GTP-loading determines Rho migratory-function in T cells. J Immunol 179:6024–6032PubMedGoogle Scholar
  120. 120.
    Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Niederwieser G, Hartung HP, Archelos JJ (2002) Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology 59:990–997PubMedCrossRefGoogle Scholar
  121. 121.
    Ifergan I, Wosik K, Cayrol R, Kebir H, Auger C, Bernard M, Bouthillier A, Moumdjian R, Duquette P, Prat A (2006) Statins reduce human blood–brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann Neurol 60:45–55PubMedCrossRefGoogle Scholar
  122. 122.
    Suzumura K, Yasuhara M, Tanaka K, Suzuki T (1999) Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro. Biochem Pharmacol 57:697–703PubMedCrossRefGoogle Scholar
  123. 123.
    Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I (2005) HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J 19:1407–1421PubMedCrossRefGoogle Scholar
  124. 124.
    Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I (2004) Oral simvastatin treatment in relapsing–remitting multiple sclerosis. Lancet 363:1607–1608PubMedCrossRefGoogle Scholar
  125. 125.
    Sena A, Pedrosa R, Graca Morais M (2003) Therapeutic potential of lovastatin in multiple sclerosis. J Neurol 250:754–755PubMedCrossRefGoogle Scholar
  126. 126.
    Göppert-Mayer M (1931) Über Elementarakte mit zwei Quantensprüngen. Ann Phys 401:273–294CrossRefGoogle Scholar
  127. 127.
    Denk W, Strickler JH, Webb WW (1990) Two-photon laser scanning fluorescence microscopy. Science 248:73–76PubMedCrossRefGoogle Scholar
  128. 128.
    Williams RM, Zipfel WR, Webb WW (2001) Multiphoton microscopy in biological research. Curr Opin Chem Biol 5:603–608PubMedCrossRefGoogle Scholar
  129. 129.
    Kerr JN, Greenberg D, Helmchen F (2005) Imaging input and output of neocortical networks in vivo. Proc Natl Acad Sci USA 102:14063–14068PubMedCrossRefGoogle Scholar
  130. 130.
    Helmchen F, Fee MS, Tank DW, Denk W (2001) A miniature head-mounted two-photon microscope. high-resolution brain imaging in freely moving animals. Neuron 31:903–912PubMedCrossRefGoogle Scholar
  131. 131.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedCrossRefGoogle Scholar
  132. 132.
    Sun SW, Liang HF, Trinkaus K, Cross AH, Armstrong RC, Song SK (2006) Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum. Magn Reson Med 55:302–308PubMedCrossRefGoogle Scholar
  133. 133.
    Boretius S, Wurfel J, Zipp F, Frahm J, Michaelis T (2007) High-field diffusion tensor imaging of mouse brain in vivo using single-shot STEAM MRI. J Neurosci Methods 161:112–117PubMedCrossRefGoogle Scholar
  134. 134.
    Wuerfel J, Tysiak E, Prozorovski T, Smyth M, Mueller S, Schnorr J, Taupitz M, Zipp F (2007) Mouse model mimics multiple sclerosis in the clinico-radiological paradox. Eur J Neurosci 26:190–198PubMedCrossRefGoogle Scholar
  135. 135.
    Bendszus M, Wessig C, Schutz A, Horn T, Kleinschnitz C, Sommer C, Misselwitz B, Stoll G (2005) Assessment of nerve degeneration by gadofluorine M-enhanced magnetic resonance imaging. Ann Neurol 57:388–395PubMedCrossRefGoogle Scholar
  136. 136.
    Rogers WJ, Meyer CH, Kramer CM (2006) Technology insight: in vivo cell tracking by use of MRI. Nat Clin Pract Cardiovasc Med 3:554–562PubMedCrossRefGoogle Scholar
  137. 137.
    Nakada T (2007) Clinical application of high and ultra high-field MRI. Brain Develop 29:325–335CrossRefGoogle Scholar
  138. 138.
    Taraseviciene L, Miczak A, Apirion D (1991) The gene specifying RNase E (rne) and a gene affecting mRNA stability (ams) are the same gene. Mol Microbiol 5:851–855PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • C. Infante-Duarte
    • 1
    • 2
  • S. Waiczies
    • 1
    • 2
  • J. Wuerfel
    • 1
    • 2
  • F. Zipp
    • 1
    • 2
  1. 1.Cecilie Vogt Clinic for Neurology in the HELIOS Clinic Berlin-BuchCharité–Universitaetsmedizin BerlinBerlinGermany
  2. 2.Max Delbrueck Center for Molecular MedicineBerlinGermany

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