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Parkinson’s Disease
Volume 2011, Article ID 931572, 8 pages
http://dx.doi.org/10.4061/2011/931572
Review Article

The Degenerating Substantia Nigra as a Susceptible Region for Gene Transfer-Mediated Inflammation

Leloir Institute, IIBBA-CONICET, Avenida Patricias Argentinas 435, 1405 Buenos Aires, Argentina

Received 2 December 2010; Accepted 29 March 2011

Academic Editor: Gilles J. Guillemin

Copyright © 2011 Valeria Roca et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. T. Hatano, S. I. Kubo, S. Sato, and N. Hattori, “Pathogenesis of familial Parkinson's disease: new insights based on monogenic forms of Parkinson's disease,” Journal of Neurochemistry, vol. 111, no. 5, pp. 1075–1093, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. A. E. Lang and A. M. Lozano, “Parkinson's disease: second of two parts,” The New England Journal of Medicine, vol. 339, no. 16, pp. 1130–1143, 1998. View at Publisher · View at Google Scholar · View at Scopus
  3. A. L. Benabid, “Gene therapy for Parkinson's disease: do we have the cure?” Lancet Neurology, vol. 9, no. 12, pp. 1142–1143, 2010. View at Google Scholar
  4. M. M. McMenamin and M. J. A. Wood, “Progress and prospects: immunobiology of gene therapy for neurodegenerative disease: Prospects and risks,” Gene Therapy, vol. 17, no. 4, pp. 448–458, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. P. R. Lowenstein, K. Kroeger, and M. G. Castro, “Immunology of neurological gene therapy: how T cells modulate viral vector-mediated therapeutic transgene expression through immunological synapses,” Neurotherapeutics, vol. 4, no. 4, pp. 715–724, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. W. G. Kim, R. P. Mohney, B. Wilson, G. H. Jeohn, B. Liu, and J. S. Hong, “Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia,” Journal of Neuroscience, vol. 20, no. 16, pp. 6309–6316, 2000. View at Google Scholar · View at Scopus
  7. A. Castaño, A. J. Herrera, J. Cano, and A. Machado, “Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system,” Journal of Neurochemistry, vol. 70, no. 4, pp. 1584–1592, 1998. View at Google Scholar · View at Scopus
  8. M. C. P. Godoy, R. Tarelli, C. C. Ferrari, M. I. Sarchi, and F. J. Pitossi, “Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease,” Brain, vol. 131, no. 7, pp. 1880–1894, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. V. H. Perry, “A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation,” Journal of Neuroimmunology, vol. 90, no. 2, pp. 113–121, 1998. View at Publisher · View at Google Scholar · View at Scopus
  10. V. H. Perry, M. D. Bell, H. C. Brown, and M. K. Matyszak, “Inflammation in the nervous system,” Current Opinion in Neurobiology, vol. 5, no. 5, pp. 636–641, 1995. View at Publisher · View at Google Scholar · View at Scopus
  11. P. R. Lowenstein, R. J. Mandel, W. D. Xiong, K. Kroeger, and M. G. Castro, “Immune responses to adenovirus and adeno-associated vectors used for gene therapy of brain diseases: the role of immunological synapses in understanding the cell biology of neuroimmune interactions,” Current Gene Therapy, vol. 7, no. 5, pp. 347–360, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. P. R. Lowenstein and M. G. Castro, “Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences,” Gene Therapy, vol. 10, no. 11, pp. 946–954, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. V. H. Perry, J. A. R. Nicoll, and C. Holmes, “Microglia in neurodegenerative disease,” Nature Reviews Neurology, vol. 6, no. 4, pp. 193–201, 2010. View at Publisher · View at Google Scholar · View at Scopus
  14. M. J. Carson, T. V. Bilousova, S. S. Puntambekar, B. Melchior, J. M. Doose, and I. M. Ethell, “A rose by any other name? The potential consequences of microglial heterogeneity during CNS health and disease,” Neurotherapeutics, vol. 4, no. 4, pp. 571–579, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. C. A. Colton, “Heterogeneity of microglial activation in the innate immune response in the brain,” Journal of Neuroimmune Pharmacology, vol. 4, no. 4, pp. 399–418, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. G. W. Kreutzberg, “Microglia: a sensor for pathological events in the CNS,” Trends in Neurosciences, vol. 19, no. 8, pp. 312–318, 1996. View at Publisher · View at Google Scholar · View at Scopus
  17. C. K. Glass, K. Saijo, B. Winner, M. C. Marchetto, and F. H. Gage, “Mechanisms underlying inflammation in neurodegeneration,” Cell, vol. 140, no. 6, pp. 918–934, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. C. M. Long-Smith, A. M. Sullivan, and Y. M. Nolan, “The influence of microglia on the pathogenesis of Parkinson's disease,” Progress in Neurobiology, vol. 89, no. 3, pp. 277–287, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. E. C. Hirsch and S. Hunot, “Neuroinflammation in Parkinson's disease: a target for neuroprotection?” The Lancet Neurology, vol. 8, no. 4, pp. 382–397, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. Ouchi, S. Yagi, M. Yokokura, and M. Sakamoto, “Neuroinflammation in the living brain of Parkinson's disease,” Parkinsonism and Related Disorders, vol. 15, supplement 3, pp. S200–S204, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains,” Neurology, vol. 38, no. 8, pp. 1285–1291, 1988. View at Google Scholar · View at Scopus
  22. M. G. Tansey and M. S. Goldberg, “Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention,” Neurobiology of Disease, vol. 37, no. 3, pp. 510–518, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. B. Mirza, H. Hadberg, P. Thomsen, and T. Moos, “The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease,” Neuroscience, vol. 95, no. 2, pp. 425–432, 1999. View at Publisher · View at Google Scholar · View at Scopus
  24. A. M. Depino, C. Earl, E. Kaczmarczyk et al., “Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease,” European Journal of Neuroscience, vol. 18, no. 10, pp. 2731–2742, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. V. A. Fadok, D. L. Bratton, A. Konowal, P. W. Freed, J. Y. Westcott, and P. M. Henson, “Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF,” Journal of Clinical Investigation, vol. 110, no. 4, pp. 890–898, 1998. View at Google Scholar
  26. Y. He, T. Lee, and S. K. Leong, “6-Hydroxydopamine induced apoptosis of dopaminergic cells in the rat substantia nigra,” Brain Research, vol. 858, no. 1, pp. 163–166, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. J. B. Koprich, C. Reske-Nielsen, P. Mithal, and O. Isacson, “Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease,” Journal of Neuroinflammation, vol. 5, article 8, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. J. Saura, M. Parés, J. Bové et al., “Intranigral infusion of interleukin-1β activates astrocytes and protects from subsequent 6-hydroxydopamine neurotoxicity,” Journal of Neurochemistry, vol. 85, no. 3, pp. 651–661, 2003. View at Google Scholar · View at Scopus
  29. Z. D. Ling, D. A. Gayle, S. Y. Ma et al., “In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain,” Movement Disorders, vol. 17, no. 1, pp. 116–124, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. P. M. Carvey, Q. Chang, J. W. Lipton, and Z. Ling, “Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson's disease,” Frontiers in Bioscience, vol. 8, pp. s826–s837, 2003. View at Google Scholar · View at Scopus
  31. Y. He, S. Appel, and W. Le, “Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum,” Brain Research, vol. 909, no. 1-2, pp. 187–193, 2001. View at Publisher · View at Google Scholar · View at Scopus
  32. A. Hald and J. Lotharius, “Oxidative stress and inflammation in Parkinson's disease: is there a causal link?” Experimental Neurology, vol. 193, no. 2, pp. 279–290, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. R. Sánchez-Pernaute, A. Ferree, O. Cooper, M. Yu, A. L. Brownell, and O. Isacson, “Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease,” Journal of Neuroinflammation, vol. 1, article 6, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. D. C. Wu, V. Jackson-Lewis, M. Vila et al., “Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease,” Journal of Neuroscience, vol. 22, no. 5, pp. 1763–1771, 2002. View at Google Scholar · View at Scopus
  35. B. Liu, L. Du, and J. S. Hong, “Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation,” Journal of Pharmacology and Experimental Therapeutics, vol. 293, no. 2, pp. 607–617, 2000. View at Google Scholar · View at Scopus
  36. A. Castaño, A. J. Herrera, J. Cano, and A. Machado, “The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-α IL-1β IFN-γ,” Journal of Neurochemistry, vol. 81, no. 1, pp. 150–157, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Depino, C. Ferrari, M. C. Pott Godoy, R. Tarelli, and F. J. Pitossi, “Differential effects of interleukin-1β on neurotoxicity, cytokine induction and glial reaction in specific brain regions,” Journal of Neuroimmunology, vol. 168, no. 1-2, pp. 96–110, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. M. C. Pott Godoy, C. C. Ferrari, and F. J. Pitossi, “Nigral neurodegeneration triggered by striatal AdIL-1 administration can be exacerbated by systemic IL-1 expression,” Journal of Neuroimmunology, vol. 222, no. 1-2, pp. 29–39, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. A. L. De Lella Ezcurra, M. Chertoff, C. Ferrari, M. Graciarena, and F. Pitossi, “Chronic expression of low levels of tumor necrosis factor-α in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation,” Neurobiology of Disease, vol. 37, no. 3, pp. 630–640, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. C. C. Ferrari, M. C. Pott Godoy, R. Tarelli, M. Chertoff, A. M. Depino, and F. J. Pitossi, “Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1β in the substantia nigra,” Neurobiology of Disease, vol. 24, no. 1, pp. 183–193, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. T. A. Tran, M. K. McCoy, M. B. Sporn, and M. G. Tansey, “The synthetic triterpenoid CDDO-methyl ester modulates microglial activities, inhibits TNF production, and provides dopaminergic neuroprotection,” Journal of Neuroinflammation, vol. 5, article 14, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. M. K. McCoy, T. N. Martinez, K. A. Ruhn et al., “Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease,” Journal of Neuroscience, vol. 26, no. 37, pp. 9365–9375, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. M. K. McCoy, K. A. Ruhn, T. N. Martinez, F. E. McAlpine, A. Blesch, and M. G. Tansey, “Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats,” Molecular Therapy, vol. 16, no. 9, pp. 1572–1579, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Gerhard, N. Pavese, G. Hotton et al., “In vivo imaging of microglial activation with [C](R)-PK11195 PET in idiopathic Parkinson's disease,” Neurobiology of Disease, vol. 21, no. 2, pp. 404–412, 2006. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Mogi, M. Harada, T. Kondob et al., “Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients,” Neuroscience Letters, vol. 180, no. 2, pp. 147–150, 1994. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Mogi, M. Harada, P. Riederer, H. Narabayashi, K. Fujita, and T. Nagatsu, “Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients,” Neuroscience Letters, vol. 165, no. 1-2, pp. 208–210, 1994. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Mogi, M. Harada, T. Kondo, P. Riederer, and T. Nagatsu, “Interleukin-2 but not basic fibroblast growth factor is elevated in parkinsonian brain. Short communication,” Journal of Neural Transmision, vol. 103, no. 8-9, pp. 1077–1081, 1996. View at Google Scholar
  48. K. Imamura, N. Hishikawa, M. Sawada, T. Nagatsu, M. Yoshida, and Y. Hashizume, “Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains,” Acta Neuropathologica, vol. 106, no. 6, pp. 518–526, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. C. Barcia, M. Jimenez-Dalmaroni, K. M. Kroeger et al., “One-year expression from high-capacity adenoviral vectors in the brains of animals with pre-existing anti-adenoviral immunity: clinical implications,” Molecular Therapy, vol. 15, no. 12, pp. 2154–2163, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. C. E. Thomas, G. Schiedner, S. Kochanek, M. G. Castro, and P. R. Löwenstein, “Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with first-generation, but not with high-capacity, adenovirus vectors: toward realistic long-term neurological gene therapy for chronic diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7482–7487, 2000. View at Google Scholar · View at Scopus
  51. C. E. Thomas, G. Schiedner, S. Kochanek, M. G. Castro, and P. R. Lowenstein, “Preexisting antiadenoviral immunity is not a barrier to efficient and stable transduction of the brain, mediated by novel high-capacity adenovirus vectors,” Human Gene Therapy, vol. 12, no. 7, pp. 839–846, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. C. Barcia, C. Gerdes, W. D. Xiong et al., “mmunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells,” Neuron Glia Biology, vol. 2, no. 4, pp. 309–322, 2006. View at Google Scholar
  53. C. C. Ferrari, A. M. Depino, F. Prada et al., “Reversible demyelination, blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain,” American Journal of Pathology, vol. 165, no. 5, pp. 1827–1837, 2004. View at Google Scholar · View at Scopus
  54. D. A. Muruve, V. Pétrilli, A. K. Zaiss et al., “The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response,” Nature, vol. 452, no. 7183, pp. 103–107, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. R. J. Mandel, K. G. Rendahl, S. K. Spratt, R. O. Snyder, L. K. Cohen, and S. E. Leff, “Characterization of intrastriatal recombinant adeno-associated virus- mediated gene transfer of human tyrosine hydroxylase and human GTP- cyclohydrolase I in a rat model of Parkinson's disease,” Journal of Neuroscience, vol. 18, no. 11, pp. 4271–4284, 1998. View at Google Scholar · View at Scopus
  56. C. S. Peden, C. Burger, N. Muzyczka, and R. J. Mandel, “Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain,” Journal of Virology, vol. 78, no. 12, pp. 6344–6359, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Reimsnider, F. P. Manfredsson, N. Muzyczka, and R. J. Mandel, “Time course of transgene expression after intrastriatal pseudotyped rAAV2/1, rAAV2/2, rAAV2/5, and rAAV2/8 transduction in the rat,” Molecular Therapy, vol. 15, no. 8, pp. 1504–1511, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Y. Mastakov, K. Baer, C. W. Symes, C. B. Leichtlein, R. M. Kotin, and M. J. During, “Immunological aspects of recombinant adeno-associated virus delivery to the mammalian brain,” Journal of Virology, vol. 76, no. 16, pp. 8446–8454, 2002. View at Publisher · View at Google Scholar · View at Scopus
  59. J. L. Eberling, W. J. Jagust, C. W. Christine et al., “Results from a phase I safety trial of hAADC gene therapy for Parkinson disease,” Neurology, vol. 70, no. 21, pp. 1980–1983, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. W. J. Marks, J. L. Ostrem, L. Verhagen et al., “Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial,” The Lancet Neurology, vol. 7, no. 5, pp. 400–408, 2008. View at Publisher · View at Google Scholar · View at Scopus
  61. M. G. Kaplitt, A. Feigin, C. Tang et al., “Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial,” Lancet, vol. 369, no. 9579, pp. 2097–2105, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Feigin, M. G. Kaplitt, C. Tang et al., “Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 49, pp. 19559–19564, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. W. J. Marks Jr., R. T. Bartus, J. Siffert et al., “Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial,” The Lancet Neurology, vol. 9, no. 12, pp. 1164–1172, 2010. View at Google Scholar
  64. B. Jarraya, S. Boulet, G. S. Ralph et al., “Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia,” Science Translational Medicine, vol. 1, no. 2, p. 2ra4, 2009. View at Google Scholar
  65. A. Pichlmair, S. S. Diebold, S. Gschmeissner et al., “Tubulovesicular structures within Vesicular stomatitis virus G protein-pseudotyped lentiviral vector preparations carry DNA and stimulate antiviral responses via toll-like receptor 9,” Journal of Virology, vol. 81, no. 2, pp. 539–547, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. C. F. Valori, K. Ning, M. Wyles, and M. Azzouz, “Development and applications of non-HIV-based lentiviral vectors in neurological disorders,” Current Gene Therapy, vol. 8, no. 6, pp. 406–418, 2008. View at Publisher · View at Google Scholar · View at Scopus
  67. B. Georgievska, D. Kirik, and A. Björklund, “Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system,” Journal of Neuroscience, vol. 24, no. 29, pp. 6437–6445, 2004. View at Publisher · View at Google Scholar · View at Scopus
  68. M. P. Limberis, C. L. Bell, J. Heath, and J. M. Wilson, “Activation of transgene-specific T cells following lentivirus-mediated gene delivery to mouse lung,” Molecular Therapy, vol. 18, no. 1, pp. 143–150, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. M. Vroemen, N. Weidner, and A. Blesch, “Loss of gene expression in lentivirus- and retrovirus-transduced neural progenitor cells is correlated to migration and differentiation in the adult spinal cord,” Experimental Neurology, vol. 195, no. 1, pp. 127–139, 2005. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Sugama, L. Yang, B. P. Cho et al., “Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice,” Brain Research, vol. 964, no. 2, pp. 288–294, 2003. View at Publisher · View at Google Scholar · View at Scopus
  71. H. Y. Chung, H. J. Kim, J. W. Kim, and B. P. Yu, “The inflammation hypothesis of aging: molecular modulation by calorie restriction,” Annals of the New York Academy of Sciences, vol. 928, pp. 327–335, 2001. View at Google Scholar · View at Scopus
  72. C. Pelegrí, A. M. Canudas, J. del Valle et al., “Increased permeability of blood-brain barrier on the hippocampus of a murine model of senescence,” Mechanisms of Ageing and Development, vol. 128, no. 9, pp. 522–528, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. E. J. McMahon, S. L. Bailey, C. V. Castenada, H. Waldner, and S. D. Miller, “Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis,” Nature Medicine, vol. 11, no. 3, pp. 335–339, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. L. C. Johnston, X. Su, K. Maguire-Zeiss et al., “Human interleukin-10 gene transfer is protective in a rat model of parkinson's disease,” Molecular Therapy, vol. 16, no. 8, pp. 1392–1399, 2008. View at Publisher · View at Google Scholar · View at Scopus