Immune-Based Cell Therapy for Acute and Chronic Neurodegeneratlve Disorders

  • M. Schwartz
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 11)

5.7 Concluding Remarks

Our findings show that CNS homeostasis is controlled not only locally, but also systemically by the adaptive arm of the immune response directed against antigens residing at the site of glutamate stress. They also provide the first direct evidence that stress-induced immune responses mediate an ongoing dialog between T cells and CNS tissue. As glutamate is a key player in brain activity, and lack of its proper regulation a key factor in cognitive, neural, psychogenic, and neurodegenerative disorders, the novel concept of immune system participation in glutamate regulation might represent a landmark in our understanding of how the body controls the brain and the development of therapies, not only for an excess but also for a deficiency of glutamate.


Spinal Cord Injury Amyotrophic Lateral Sclerosis Traumatic Spinal Cord Injury Glutamate Toxicity Interphotoreceptor Retinoid Binding Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adamus G, Chan CC (2002) Experimental autoimmune uveitides: multiple antigens, diverse diseases. Int Rev Immunol 21:209–229PubMedCrossRefGoogle Scholar
  2. Aharoni R, Teitelbaum D, Sela M, Arnon R (1997) Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci 94:10821–10826PubMedCrossRefGoogle Scholar
  3. Angelov DN, Waibel S, Guntinas-Lichius O, Lenzen M, Neiss WF, Tomov TL, Yoles E, Kipnis J, Schori H, Reuter A, Ludolph A, Schwartz M (2003) Therapeutic vaccine for acute and chronic motor neuron diseases: implications for ALS. Proc Natl Acad Sci 100:4790–4795PubMedCrossRefGoogle Scholar
  4. Arnon R, Sela M, Teitelbaum D (1996) New insights into the mechanism of action of copolymer 1 in experimental allergic encephalomyelitis and multiple sclerosis. J Neurol 243:S8–S13PubMedCrossRefGoogle Scholar
  5. Avichezer D, Chan CC, Silver PB, Wiggert B, Caspi RR (2000) Residues 1-20 of IRBP and whole IRBP elicit different uveitogenic and immunological responses in interferon gamma deficient mice. Exp Eye Res 71:111–118PubMedCrossRefGoogle Scholar
  6. 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
  7. Bethea JR, Dietrich WD (2002) Targeting the host inflammatory response in traumatic spinal cord injury. Curr Opin Neurol 15:355–360PubMedCrossRefGoogle Scholar
  8. Bethea JR, Nagashima H, Acosta MC, Briceno C, Gomez F, Marcillo AE, Loor K, Green J, Dietrich WD (1999) Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 16:851–863PubMedCrossRefGoogle Scholar
  9. Bjartmar C, Trapp BD (2001) Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 14:271–278PubMedCrossRefGoogle Scholar
  10. Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD (2001) Axonal loss in normal appearing white matter in a patient with acute MS. Neurology 57:1248–1252PubMedGoogle Scholar
  11. Blaugrund E, Lavie V, Cohen L, Solomon A, Schreyer DJ, Schwartz M (1993) Axonal regeneration is associated with glial migration: comparison between the injured optic nerves of fish and rats. J Comp Neurol 330:105–112PubMedCrossRefGoogle Scholar
  12. Bomstein Y, Marder JB, Vitner K, Smirnov L, Lisaey G, Butovsky O, Fulga V, Yoles E (2003) Features of skin-coincubated macrophages that promote recovery from spinal cord injury. J Neuroimmunol 142:10–16PubMedCrossRefGoogle Scholar
  13. Butovsky O, Hauben E, Schwartz M (2001) Morphological aspects of spinal cord autoimmune neuroprotection: colocalization of T cells with B7-2 (CD86) and prevention of cyst formation. FASEB J 15:1065–1067PubMedGoogle Scholar
  14. Carlson SL, Parrish ME, Springer JE, Doty K, Dossett L (1998) Acute inflammatory response in spinal cord following impact injury. Exp Neurol 151:77–88PubMedCrossRefGoogle Scholar
  15. Constantini S, Young W (1994) The effects of methylprednisolone and the ganglioside GM 1 in acute spinal cord injury in rats. J Neurosurg 80:97–111PubMedCrossRefGoogle Scholar
  16. David S, Bouchard C, Tsatas O, Giftochristos N (1990) Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron 5:463–469PubMedCrossRefGoogle Scholar
  17. De Stefano N, Narayanan S, Francis GS, Amaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65–70PubMedCrossRefGoogle Scholar
  18. Dusart I, Schwab ME (1994) Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 6:712–724PubMedCrossRefGoogle Scholar
  19. Fauser S, Nguyen TD, Bekure K, Schluesener HJ, Meyermann R (2001) Differential activation of microglial cells in local and remote areas of IRBP1169-1191-induced rat uveitis. Acta Neuropathol (Berl) 101:565–571Google Scholar
  20. Fisher J, Levkovitch-Verbin H, Schori H, Yoles E, Butovsky O, Kaye JF, Ben-Nun A, Schwartz M (2001a) Vaccination for neuroprotection in the mouse optic nerve: implications for optic neuropathies. J Neurosci 21:136–142PubMedGoogle Scholar
  21. Fisher J, Mizrahi T, Schori H, Yoles E, Levkovitch-Verbin H, Haggiag S, Revel M, Schwartz M (2001b) Increased post-traumatic survival of neurons in IL-6-knockout mice in a background of EAE susceptibility. J Neuroimmunol 119:1–9PubMedCrossRefGoogle Scholar
  22. Fitch MT, Doller C, Combs CK, Landreth GE, Silver J (1999) Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 19:8182PubMedGoogle Scholar
  23. Ghimikar RS, Lee YL, Eng LF (2001) Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat. J Neurosci Res 64:582–589CrossRefGoogle Scholar
  24. Hafler DA (2002) Degeneracy, as opposed to specificity, in immunotherapy. J Clin Invest 109:581–584PubMedCrossRefGoogle Scholar
  25. Hauben E, Schwartz M (2003) Therapeutic vaccination for spinal cord injury: Helping the body to cure itself. Trends Pharmacol Sci 24:7–12PubMedCrossRefGoogle Scholar
  26. Hauben E, Nevo U, Yoles E, Moalem G, Agranov E, Mor F, Akselrod S, Neeman M, Cohen IR, Schwartz M (2000a) Autoimmune T cells as potential neuroprotective therapy for spinal cord injury. Lancet 355:286–287PubMedCrossRefGoogle Scholar
  27. Hauben E, Butovsky O, Nevo U, Yoles E, Moalem G, Agranov E, Mor F, Leibowitz-Amit R, Pevsner E, Akselrod S, Neeman M, Cohen IR, Schwartz M (2000b) Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 20:6421–6430PubMedGoogle Scholar
  28. Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smimov I, Steinman L, Schwartz M (2001) Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest 108:591–599PubMedCrossRefGoogle Scholar
  29. Hauben E, Gothilf A, Cohen A, Butovsky O, Nevo U, Smimov 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
  30. Hirschberg DL, Yoles E, Belkin M, Schwartz M (1994) Inflammation after axonal injury has conflicting consequences for recovery of function: rescue of spared axons is impaired but regeneration is supported. J Neuroimmunol 50:9–16PubMedCrossRefGoogle Scholar
  31. Hofstetter HH, Sewell DL, Liu F, Sandor M, Forsthuber T, Lehmann PV, Fabry Z (2003) Autoreactive T cells promote post-traumatic healing in the central nervous system. J Neuroimmunol 134:25–34PubMedCrossRefGoogle Scholar
  32. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci 99:1604–1609PubMedCrossRefGoogle Scholar
  33. Kipnis J, Schwartz M (2002) Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders. Trends Mol Med 8:319–323PubMedCrossRefGoogle Scholar
  34. Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, Cohen IR, Schwartz M (2000) T cell immunity to copolymer 1 confers neuroprotection in the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci USA 97:7446–7451PubMedCrossRefGoogle Scholar
  35. Kipnis J, Yoles E, Schori H, Hauben E, Shaked I, Schwartz M (2001) Neuronal survival after CNS insult is determined by a genetically encoded autoimmune response. J Neurosci 21:4564–4571PubMedGoogle Scholar
  36. Kipnis J, Mizrahi T, Yoles E, Ben-Nun A, Schwartz M (2002a) Myelin specific Thl cells are necessary for post-traumatic protective autoimmunity. J Neuroimmunol 130:78–85PubMedCrossRefGoogle Scholar
  37. Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M (2002b) Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci 99:15620–15625PubMedCrossRefGoogle Scholar
  38. Kipnis J, Nevo U, Panikashvili D, Alexanderovich A, Yoles E, Akselrod S, Shohami E, Schwartz M (2003) Therapeutic Vaccination for closed head injury. J Neurotrauma 20:559–569PubMedCrossRefGoogle Scholar
  39. Lazarov-Spiegler O, Solomon AS, Schwartz M (1998) Peripheral nervestimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optic nerve. Glia 24:329–337PubMedCrossRefGoogle Scholar
  40. Lotan M, Schwartz M (1994) Cross talk between the immune system and the nervous system in response to injury: implications for regeneration. FASEBJ 8:1026–1033Google Scholar
  41. Maragakis NJ, Rothstein JD (2001) Glutamate transporters in neurologic disease. Arch Neurol 58:365–370PubMedCrossRefGoogle Scholar
  42. Mautes AE, Weinzierl MR, Donovan F, Noble LJ (2000) Vascular events after spinal cord injury: contribution to secondary pathogenesis. Phys Ther 80:673–687PubMedGoogle Scholar
  43. Mizrahi T, Hauben E, Schwartz M (2002) The tissue-specific self-pathogen is the protective self-antigen: The case of uveitis. J Immunol 169:5971–5977PubMedGoogle Scholar
  44. 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. Nat Med 5:49–55PubMedCrossRefGoogle Scholar
  45. Moalem G, Gdalyahu A, Shani Y, Otten U, Lazarovici P, Cohen IR, Schwartz M (2000) Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J Autoimmun 15:331–345PubMedCrossRefGoogle Scholar
  46. Nevo U, Hauben E, Yoles E, Agranov E, Akselrod S, Schwartz M, Neeman M (2001) Diffusion anisotropy MRI for quantitative assessment of recovery in injured rat spinal cord. Magn Reson Med 45:1–9PubMedCrossRefGoogle Scholar
  47. Nevo U, Kipnis J, Golding L, Shaked I, Neumann A, Akselrod S, Schwartz M (2003) Autoimmunity as a special case of immunity: removing threats from within. Trends Mol Med 9:88–93PubMedCrossRefGoogle Scholar
  48. Ousman SS, David S (2001) MIP-lalpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci 21:4649–4656PubMedGoogle Scholar
  49. Perry VH, Brown MC (1992) Macrophages and nerve regeneration. Curr Opin Neurobiol 2:679–682PubMedCrossRefGoogle Scholar
  50. Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT (1999) Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 158:351–365PubMedCrossRefGoogle Scholar
  51. Rapalino O, Lazarov-Spiegler 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. Nat Med 4:814–821PubMedCrossRefGoogle Scholar
  52. Schnell L, Feam S, Klassen H, Schwab ME, Perry VH (1999) Acute inflammatory responses to mechanical lesions in the CNS: differences between brain and spinal cord. Eur J Neurosci 11:3648–3658PubMedCrossRefGoogle Scholar
  53. Schori H, Kipnis J, Yoles E, WoldeMussie E, Ruiz G, Wheeler LA, Schwartz M (2001) Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc Natl Acad Sci 98:3398–3403PubMedCrossRefGoogle Scholar
  54. Schori H, Yoles E, Wheeler LA, Schwartz M (2002) Immune related mechanisms participating in resistance and susceptibility to glutamate toxicity. Eur J Neurosci 16:557–564PubMedCrossRefGoogle Scholar
  55. Schwartz M, Kipnis J (2002a) Autoimmunity in alert: naturally occurring regulatory CD4+CD25+ T cells as part of the evolutionary compromise between a “need” and a “risk.” Trends Immunol 23:530–534PubMedCrossRefGoogle Scholar
  56. Schwartz M, Kipnis J (2002b) Multiple sclerosis as a by-product of the failure to sustain protective autoimmunity: A paradigm shift. Neuroscientist 8:405–413PubMedCrossRefGoogle Scholar
  57. Schwartz M, Shaked I, Fisher J, Mizrahi T, Schori H (2003) Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends Neurosci 26:297–302PubMedCrossRefGoogle Scholar
  58. Sela M, Teitelbaum D (2001) Glatiramer acetate in the treatment of multiple sclerosis. Expert Opin Pharmacother 2:1149–1165PubMedCrossRefGoogle Scholar
  59. Shevach EM (2002) CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMedGoogle Scholar
  60. Sicard RE (2002) Differential inflammatory and immunological responses in tissue regeneration and repair. Ann NY Acad Sci 961:368–371PubMedCrossRefGoogle Scholar
  61. Steinman L (2001) Multiple sclerosis: a two-stage disease. Nat Immunol 2:762–764PubMedCrossRefGoogle Scholar
  62. Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A, Kuchroo V, Cohen IR, Weiner H, Schwartz M (2001) Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 21:3740–3748PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • M. Schwartz
    • 1
  1. 1.Department of Neurobiology, Building for Brain ResearchWeizmann Institute of ScienceRehovotIsrael

Personalised recommendations