Pathways towards an effective immunotherapy for Parkinson’s disease

References

• Jellinger KA. Formation and development of Lewy pathology: a critical update. J. Neurol.256(Suppl. 3), 270–279 (2009).
   PubMed Web of Science ®Google Scholar
• Jellinger KA. α-synuclein pathology in Parkinson's and Alzheimer's disease brain: incidence and topographic distribution – a pilot study. Acta Neuropathol.106(3), 191–201 (2003).
   PubMedGoogle Scholar
• Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J. Neurol. Sci.20(4), 415–455 (1973).
   PubMed Web of Science ®Google Scholar
• Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet373(9680), 2055–2066 (2009).
   PubMed Web of Science ®Google Scholar
• Mercuri NB, Bernardi G. The ‘magic’ of L-dopa: why is it the gold standard Parkinson’s disease therapy? Trends Pharmacol. Sci.26(7), 341–344 (2005).
   PubMed Web of Science ®Google Scholar
• Silver DE, Ruggieri S. Initiating therapy for Parkinson’s disease. Neurology50(Suppl. 6), S18–S22 (1998).
   Google Scholar
• Fahn S. ‘On-off’ phenomenon with levodopa therapy in Parkinsonism. Clinical and pharmacologic correlations and the effect of intramuscular pyridoxine. Neurology24(5), 431–441 (1974).
   PubMed Web of Science ®Google Scholar
• Hutton JT, Morris JL. Long-acting carbidopa–levodopa in the management of moderate and advanced Parkinson’s disease. Neurology42(1 Suppl. 1), 51–56 (1992).
   PubMed Web of Science ®Google Scholar
• Rascol O, Lozano A, Stern M, Poewe W. Milestones in Parkinson’s disease therapeutics. Mov. Disord.26(6), 1072–1082 (2011).
   PubMed Web of Science ®Google Scholar
• Clarkson ED. Fetal tissue transplantation for patients with Parkinson’s disease: a database of published clinical results. Drugs Aging18(10), 773–785 (2001).
   PubMed Web of Science ®Google Scholar
• Lindvall O, Rehncrona S, Brundin P et al. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch. Neurol.46(6), 615–631 (1989).
   PubMed Web of Science ®Google Scholar
• Freed CR, Greene PE, Breeze RE et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med.344(10), 710–719 (2001).
   PubMed Web of Science ®Google Scholar
• Olanow CW, Goetz CG, Kordower JH et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann. Neurol.54(3), 403–414 (2003).
   PubMed Web of Science ®Google Scholar
• Olanow CW, Kordower JH, Lang AE, Obeso JA. Dopaminergic transplantation for Parkinson’s disease: current status and future prospects. Ann. Neurol.66(5), 591–596 (2009).
   PubMedGoogle Scholar
• Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med.14(5), 504–506 (2008).
   PubMed Web of Science ®Google Scholar
• Dawson TM. Non-autonomous cell death in Parkinson’s disease. Lancet Neurol.7(6), 474–475 (2008).
   PubMedGoogle Scholar
• Ferrari G, Minozzi MC, Toffano G, Leon A, Skaper SD. Basic fibroblast growth factor promotes the survival and development of mesencephalic neurons in culture. Dev. Biol.133(1), 140–147 (1989).
   PubMed Web of Science ®Google Scholar
• Knusel B, Michel PP, Schwaber JS, Hefti F. Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J. Neurosci.10(2), 558–570 (1990).
   PubMed Web of Science ®Google Scholar
• Park TH, Mytilineou C. Protection from 1-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP(+)-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF. Brain Res.599(1), 83–97 (1992).
   PubMedGoogle Scholar
• Hyman C, Hofer M, Barde YA et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature350(6315), 230–232 (1991).
   PubMed Web of Science ®Google Scholar
• Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science260(5111), 1130–1132 (1993).
   PubMed Web of Science ®Google Scholar
• Beck KD, Valverde J, Alexi T et al. Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature373(6512), 339–341 (1995).
   PubMed Web of Science ®Google Scholar
• Gash DM, Zhang Z, Ovadia A et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature380(6571), 252–255 (1996).
   PubMed Web of Science ®Google Scholar
• Kordower JH, Emborg ME, Bloch J et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science290(5492), 767–773 (2000).
   PubMed Web of Science ®Google Scholar
• Hong M, Mukhida K, Mendez I. GDNF therapy for Parkinson’s disease. Expert Rev. Neurother.8(7), 1125–1139 (2008).
   PubMedGoogle Scholar
• Rangasamy SB, Soderstrom K, Bakay RA, Kordower JH. Neurotrophic factor therapy for Parkinson’s disease. Prog. Brain Res.184, 237–264 (2010).
   PubMed Web of Science ®Google Scholar
• Kordower JH, Palfi S, Chen EY et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann. Neurol.46(3), 419–424 (1999).
   PubMed Web of Science ®Google Scholar
• Nutt JG, Burchiel KJ, Comella CL et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology60(1), 69–73 (2003).
   PubMed Web of Science ®Google Scholar
• Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J. Neurosurg.102(2), 216–222 (2005).
   PubMed Web of Science ®Google Scholar
• Gill SS, Patel NK, Hotton GR et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med.9(5), 589–595 (2003).
   PubMed Web of Science ®Google Scholar
• Luo XG, Ding JQ, Chen SD. Microglia in the aging brain: relevance to neurodegeneration. Mol. Neurodegener.5, 12 (2010).
   PubMedGoogle Scholar
• Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol.119(1), 89–105 (2010).
   PubMed Web of Science ®Google Scholar
• Kosloski LM, Ha DM, Hutter JA et al. Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J. Neurochem.114(5), 1261–1276 (2010).
   PubMedGoogle Scholar
• Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol.54(Pt 1), 1–13 (1989).
   PubMedGoogle Scholar
• Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu. Rev. Immunol.20, 197–216 (2002).
   PubMed Web of Science ®Google Scholar
• Amor S, Puentes F, Baker D, Van Der Valk P. Inflammation in neurodegenerative diseases. Immunology129(2), 154–169 (2010).
   PubMed Web of Science ®Google Scholar
• McGeer PL, Yasojima K, McGeer EG. Inflammation in Parkinson’s disease. Adv. Neurol.86, 83–89 (2001).
   PubMed Web of Science ®Google Scholar
• Smith PF. Inflammation in Parkinson’s disease: an update. Curr. Opin. Investig. Drugs9(5), 478–484 (2008).
   PubMedGoogle Scholar
• Tansey MG, Goldberg MS. Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis.37(3), 510–518 (2010).
   PubMed Web of Science ®Google Scholar
• Siffrin V, Brandt AU, Herz J, Zipp F. New insights into adaptive immunity in chronic neuroinflammation. Adv. Immunol.96, 1–40 (2007).
   PubMed Web of Science ®Google Scholar
• McGeer PL, McGeer EG. Glial reactions in Parkinson’s disease. Mov. Dis.23(4), 474–483 (2008).
   PubMed Web of Science ®Google Scholar
• Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol.8(4), 382–397 (2009).
   PubMed Web of Science ®Google Scholar
• Perry VH. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol.120(3), 277–286 (2010).
   PubMed Web of Science ®Google Scholar
• Liu B, Gao HM, Hong JS. Parkinson’s disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation. Environ. Health Perspect.111(8), 1065–1073 (2003).
   PubMed Web of Science ®Google Scholar
• Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat. Med.10(Suppl.), S18–S25 (2004).
   PubMed Web of Science ®Google Scholar
• Blasko I, Grubeck-Loebenstein B. Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer’s disease. Drugs Aging20(2), 101–113 (2003).
   PubMedGoogle Scholar
• Klegeris A, McGeer PL. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Curr. Alzheimer Res.2(3), 355–365 (2005).
   PubMedGoogle Scholar
• Rich JB, Rasmusson DX, Folstein MF, Carson KA, Kawas C, Brandt J. Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease. Neurology45(1), 51–55 (1995).
   PubMed Web of Science ®Google Scholar
• in t’ Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med.345(21), 1515–1521 (2001).
   PubMed Web of Science ®Google Scholar
• Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JC. Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology59(6), 880–886 (2002).
   PubMed Web of Science ®Google Scholar
• Becker C, Jick SS, Meier CR. NSAID use and risk of Parkinson disease: a population-based case–control study. Eur. J. Neurol.18(11), 1336–1342 (2011).
   PubMedGoogle Scholar
• Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology76(10), 863–869 (2011).
   PubMed Web of Science ®Google Scholar
• Manthripragada AD, Schernhammer ES, Qiu J et al. Non-steroidal anti-inflammatory drug use and the risk of Parkinson’s disease. Neuroepidemiology36(3), 155–161 (2011).
   PubMedGoogle Scholar
• Cunningham C, Skelly DT. Non-steroidal anti-inflammatory drugs and cognitive function: are prostaglandins at the heart of cognitive impairment in dementia and delirium? J. Neuroimmune Pharmacol. doi:10.1007/s11481-011-9312-5 (2011) (Epub ahead of print).
   PubMedGoogle Scholar
• Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science308(5726), 1314–1318 (2005).
   PubMed Web of Science ®Google Scholar
• Davalos D, Grutzendler J, Yang G et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci.8(6), 752–758 (2005).
   PubMed Web of Science ®Google Scholar
• Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics7(4), 354–365 (2010).
   PubMed Web of Science ®Google Scholar
• Zhang SC, Fedoroff S. Neuron-microglia interactions in vitro. Acta Neuropathol.91(4), 385–395 (1996).
   PubMedGoogle Scholar
• Glezer I, Simard AR, Rivest S. Neuroprotective role of the innate immune system by microglia. Neuroscience147(4), 867–883 (2007).
   PubMedGoogle Scholar
• Giulian D, Baker TJ, Shih LC, Lachman LB. Interleukin 1 of the central nervous system is produced by ameboid microglia. J. Exp. Med.164(2), 594–604 (1986).
   PubMed Web of Science ®Google Scholar
• Sawada M, Kondo N, Suzumura A, Marunouchi T. Production of tumor necrosis factor-α by microglia and astrocytes in culture. Brain Res.491(2), 394–397 (1989).
   PubMed Web of Science ®Google Scholar
• Elkabes S, Dicicco-Bloom EM, Black IB. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci.16(8), 2508–2521 (1996).
   PubMed Web of Science ®Google Scholar
• Heese K, Hock C, Otten U. Inflammatory signals induce neurotrophin expression in human microglial cells. J. Neurochem.70(2), 699–707 (1998).
   PubMed Web of Science ®Google Scholar
• Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity32(5), 593–604 (2010).
   PubMed Web of Science ®Google Scholar
• Rock RB, Gekker G, Hu S et al. Role of microglia in central nervous system infections. Clin. Microbiol. Rev.17(4), 942–964, (2004).
   PubMed Web of Science ®Google Scholar
• Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci.29(43), 13435–13444 (2009).
   PubMed Web of Science ®Google Scholar
• McGeer PL, Itagaki S, McGeer EG. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol.76(6), 550–557 (1988).
   PubMed Web of Science ®Google Scholar
• Muhleisen H, Gehrmann J, Meyermann R. Reactive microglia in Creutzfeldt–Jakob disease. Neuropathol. Appl. Neurobiol.21(6), 505–517 (1995).
   PubMedGoogle Scholar
• Gonzalez-Scarano F, Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu. Rev. Neurosci.22, 219–240 (1999).
   PubMed Web of Science ®Google Scholar
• Engelhardt JI, Appel SH. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch. Neurol.47(11), 1210–1216 (1990).
   PubMed Web of Science ®Google Scholar
• Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH. Alzheimer’s disease. A double-labeling immunohistochemical study of senile plaques. Am. J. Pathol.132(1), 86–101 (1988).
   PubMed Web of Science ®Google Scholar
• Mattiace LA, Davies P, Yen SH, Dickson DW. Microglia in cerebellar plaques in Alzheimer’s disease. Acta Neuropathol.80(5), 493–498 (1990).
   PubMedGoogle Scholar
• McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology38(8), 1285–1291 (1988).
   PubMed Web of Science ®Google Scholar
• Crystal H, Dickson D, Fuld P et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology38(11), 1682–1687 (1988).
   PubMed Web of Science ®Google Scholar
• Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature388(6645), 839–840 (1997).
   PubMed Web of Science ®Google Scholar
• Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc. Natl Acad. Sci. USA95(11), 6469–6473 (1998).
   PubMed Web of Science ®Google Scholar
• Goldman JE, Yen SH, Chiu FC, Peress NS. Lewy bodies of Parkinson’s disease contain neurofilament antigens. Science221(4615), 1082–1084 (1983).
   PubMed Web of Science ®Google Scholar
• Jellinger KA. Lewy body disorders. In: Degenerative Diseases of the Nervous System. Youdim MBH (Ed.). Springer Science, New York, NY, USA, 270–343 (2007).
   Google Scholar
• Shimura H, Schlossmacher MG, Hattori N et al. Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson’s disease. Science293(5528), 263–269 (2001).
   PubMed Web of Science ®Google Scholar
• Fujiwara H, Hasegawa M, Dohmae N et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol.4(2), 160–164 (2002).
   PubMed Web of Science ®Google Scholar
• Giasson BI, Duda JE, Murray IV et al. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science290(5493), 985–989 (2000).
   PubMed Web of Science ®Google Scholar
• Uversky VN, Yamin G, Munishkina LA et al. Effects of nitration on the structure and aggregation of α-synuclein. Brain Res. Mol. Brain Res.134(1), 84–102 (2005).
   PubMedGoogle Scholar
• Cavallarin N, Vicario M, Negro A. The role of phosphorylation in synucleinopathies: focus on Parkinson’s disease. CNS Neurol. Disord. Drug Targets9(4), 471–481 (2010).
   PubMed Web of Science ®Google Scholar
• Lee SJ. Origins and effects of extracellular α-synuclein: implications in Parkinson’s disease. J. Mol. Neurosci.34(1), 17–22 (2008).
   PubMedGoogle Scholar
• Good PF, Hsu A, Werner P, Perl DP, Olanow CW. Protein nitration in Parkinson’s disease. J. Neuropathol. Exp. Neurol.57(4), 338–342 (1998).
   PubMed Web of Science ®Google Scholar
• Beach TG, Adler CH, Sue LI et al. Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol.119(6), 689–702 (2010).
   PubMedGoogle Scholar
• Koprich JB, Johnston TH, Reyes MG, Sun X, Brotchie JM. Expression of human A53T α-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson’s disease. Mol. Neurodegener.5, 43 (2010).
   PubMed Web of Science ®Google Scholar
• Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. α-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int. J. Biochem. Cell Biol.41(10), 2015–2024 (2009).
   PubMed Web of Science ®Google Scholar
• Polymeropoulos MH, Higgins JJ, Golbe LI et al. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science274(5290), 1197–1199 (1996).
   PubMed Web of Science ®Google Scholar
• Polymeropoulos MH, Lavedan C, Leroy E et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science276(5321), 2045–2047 (1997).
   PubMed Web of Science ®Google Scholar
• Kruger R, Kuhn W, Muller T et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat. Genet.18(2), 106–108 (1998).
   PubMed Web of Science ®Google Scholar
• Zarranz JJ, Alegre J, Gomez-Esteban JC et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol.55(2), 164–173 (2004).
   PubMed Web of Science ®Google Scholar
• Chartier-Harlin MC, Kachergus J, Roumier C et al. α-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet364(9440), 1167–1169 (2004).
   PubMed Web of Science ®Google Scholar
• Singleton AB, Farrer M, Johnson J et al. α-Synuclein locus triplication causes Parkinson’s disease. Science302(5646), 841 (2003).
   PubMed Web of Science ®Google Scholar
• Uversky VN. Neuropathology, biochemistry, and biophysics of α-synuclein aggregation. J. Neurochem.103(1), 17–37 (2007).
   PubMed Web of Science ®Google Scholar
• Narhi L, Wood SJ, Steavenson S et al. Both familial Parkinson’s disease mutations accelerate α-synuclein aggregation. J. Biol. Chem.274(14), 9843–9846 (1999).
   PubMed Web of Science ®Google Scholar
• Li J, Uversky VN, Fink AL. Effect of familial Parkinson’s disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human α-synuclein. Biochemistry40(38), 11604–11613 (2001).
   PubMed Web of Science ®Google Scholar
• Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS. Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J. Neurosci.20(16), 6309–6316 (2000).
   PubMed Web of Science ®Google Scholar
• Theodore S, Cao S, McLean PJ, Standaert DG. Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol.67(12), 1149–1158 (2008).
   PubMed Web of Science ®Google Scholar
• Zhang W, Wang T, Pei Z et al. Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J.19(6), 533–542 (2005).
   PubMed Web of Science ®Google Scholar
• Reynolds AD, Kadiu I, Garg SK et al. Nitrated α-synuclein and microglial neuroregulatory activities. J. Neuroimmune Pharm.3(2), 59–74 (2008).
   PubMedGoogle Scholar
• Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM. Neuroinflammation and oxidation/nitration of α-synuclein linked to dopaminergic neurodegeneration. Neuroscience28(30), 7687–7698 (2008).
   PubMedGoogle Scholar
• Hunot S, Boissiere F, Faucheux B et al. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience72(2), 355–363 (1996).
   PubMed Web of Science ®Google Scholar
• Shavali S, Combs CK, Ebadi M. Reactive macrophages increase oxidative stress and α-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson’s disease. Neurochem. Res.31(1), 85–94 (2006).
   PubMed Web of Science ®Google Scholar
• Rentzos M, Nikolaou C, Andreadou E et al. Circulating interleukin-15 and RANTES chemokine in Parkinson’s disease. Acta Neurol. Scand.116(6), 374–379 (2007).
   PubMed Web of Science ®Google Scholar
• Rentzos M, Nikolaou C, Andreadou E et al. Circulating interleukin-10 and interleukin-12 in Parkinson’s disease. Acta Neurol. Scand.119(5), 332–337 (2009).
   PubMed Web of Science ®Google Scholar
• Teismann P, Tieu K, Choi DK et al. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc. Natl Acad. Sci. USA100(9), 5473–5478 (2003).
   PubMed Web of Science ®Google Scholar
• Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci. Lett.202(1–2), 17–20 (1995).
   PubMed Web of Science ®Google Scholar
• Reynolds AD, Glanzer JG, Kadiu I et al. Nitrated α-synuclein-activated microglial profiling for Parkinson’s disease. J. Neurochem.104(6), 1504–1525 (2008).
   PubMed Web of Science ®Google Scholar
• Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood–brain barrier pathology in Alzheimer’s and Parkinson’s disease: implications for drug therapy. Cell Transplant16(3), 285–299 (2007).
   PubMed Web of Science ®Google Scholar
• Wong D, Prameya R, Dorovini-Zis K. In vitro adhesion and migration of T lymphocytes across monolayers of human brain microvessel endothelial cells: regulation by ICAM-1, VCAM-1, E-selectin and PECAM-1. J. Neuropathol. Exp. Neurol.58(2), 138–152 (1999).
   PubMedGoogle Scholar
• Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol.173(6), 3916–3924 (2004).
   PubMed Web of Science ®Google Scholar
• Aloisi F, Ria F, Columba-Cabezas S, Hess H, Penna G, Adorini L. Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation. Eur. J. Immunol.29(9), 2705–2714 (1999).
   PubMed Web of Science ®Google Scholar
• McGeer EG, McGeer PL. Inflammatory processes in Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry27(5), 741–749 (2003).
   PubMed Web of Science ®Google Scholar
• Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol. Aging9(4), 339–349 (1988).
   PubMed Web of Science ®Google Scholar
• Togo T, Akiyama H, Iseki E et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J. Neuroimmunol.124(1–2), 83–92 (2002).
   PubMed Web of Science ®Google Scholar
• Farkas E, De Jong GI, Apro E, De Vos RA, Steur EN, Luiten PG. Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer’s disease, Parkinson’s disease, and experimental hypertension. What is the functional link? Ann. NY Acad. Sci.903, 72–82 (2000).
   PubMed Web of Science ®Google Scholar
• Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol.29(1), 58–69 (1948).
   PubMed Web of Science ®Google Scholar
• Benner EJ, Banerjee R, Reynolds AD et al. Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS ONE3(1), e1376 (2008).
   PubMed Web of Science ®Google Scholar
• Brochard V, Combadiere B, Prigent A et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest.119(1), 182–192 (2009).
   PubMed Web of Science ®Google Scholar
• McRae-Degueurce A, Rosengren L, Haglid K et al. Immunocytochemical investigations on the presence of neuron-specific antibodies in the CSF of Parkinson’s disease cases. Neurochem. Res.13(7), 679–684 (1988).
   PubMedGoogle Scholar
• Maetzler W, Berg D, Synofzik M et al. Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of lewy body-associated dementias. J. Alzheimers Dis.26(1), 171–179 (2011).
   PubMedGoogle Scholar
• Fiszer U, Mix E, Fredrikson S, Kostulas V, Link H. Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol. Scand.90(3), 160–166 (1994).
   PubMedGoogle Scholar
• Hisanaga K, Asagi M, Itoyama Y, Iwasaki Y. Increase in peripheral CD4 bright+ CD8 dull+ T cells in Parkinson disease. Arch. Neurol.58(10), 1580–1583 (2001).
   PubMed Web of Science ®Google Scholar
• Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat. Disord.11(8), 493–498 (2005).
   PubMed Web of Science ®Google Scholar
• Fiszer U. Does Parkinson’s disease have an immunological basis? The evidence and its therapeutic implications. Biodrugs15(6), 351–355 (2001).
   PubMedGoogle Scholar
• Bradbury J. Immunotherapy for Parkinson’s disease: a developing therapeutic strategy. Drug Discov. Today10(16), 1075–1076 (2005).
   PubMedGoogle Scholar
• Klegeris A, McGeer EG, McGeer PL. Therapeutic approaches to inflammation in neurodegenerative disease. Curr. Opin. Neurol.20(3), 351–357 (2007).
   PubMed Web of Science ®Google Scholar
• Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener. Dis.5(3–4), 194–196 (2008).
   PubMed Web of Science ®Google Scholar
• Villoslada P, Moreno B, Melero I et al. Immunotherapy for neurological diseases. Clin. Immunol.128(3), 294–305 (2008).
   PubMedGoogle Scholar
• Agbo DB, Neff F, Seitz F et al. Immunization as treatment for Parkinson’s disease. J. Neural. Transm. Suppl.73, 311–315 (2009).
   Google Scholar
• Reichert JM. Antibody-based therapeutics to watch in 2011. MAbs3(1), 76–99 (2011).
   PubMed Web of Science ®Google Scholar
• Janeway CA Jr, Medzhitov R. Introduction: the role of innate immunity in the adaptive immune response. Semin. Immunol.10(5), 349–350 (1998).
   PubMed Web of Science ®Google Scholar
• Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol.255(Suppl. 1), 3–11 (2008).
   PubMed Web of Science ®Google Scholar
• Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature400(6740), 173–177 (1999).
   PubMed Web of Science ®Google Scholar
• Weiner HL, Lemere CA, Maron R et al. Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann. Neurol.48(4), 567–579 (2000).
   PubMed Web of Science ®Google Scholar
• Janus C, Pearson J, McLaurin J et al. A β peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature408(6815), 979–982 (2000).
   PubMed Web of Science ®Google Scholar
• Morgan D, Diamond DM, Gottschall PE et al. A β peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature408(6815), 982–985 (2000).
   PubMed Web of Science ®Google Scholar
• Bard F, Cannon C, Barbour R et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med.6(8), 916–919 (2000).
   PubMed Web of Science ®Google Scholar
• Demattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A β antibody alters CNS and plasma A β clearance and decreases brain A β burden in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA98(15), 8850–8855 (2001).
   PubMed Web of Science ®Google Scholar
• Senior K. Dosing in Phase II trial of Alzheimer’s vaccine suspended. Lancet Neurol.1(1), 3 (2002).
   PubMed Web of Science ®Google Scholar
• Masliah E, Rockenstein E, Adame A et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron46(6), 857–868 (2005).
   PubMed Web of Science ®Google Scholar
• Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME(R) technology in neurodegenerative diseases: the doubling advantage. Hum. Vaccin.6(11), 64–68 (2010).
   Google Scholar
• Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol (Balt.)155(3), 1151–1164 (1995).
   PubMed Web of Science ®Google Scholar
• Sakaguchi S, Hori S, Fukui Y, Sasazuki T, Sakaguchi N, Takahashi T. Thymic generation and selection of CD25+CD4+ regulatory T cells: implications of their broad repertoire and high self-reactivity for the maintenance of immunological self-tolerance. Novartis Found. Symp.252, 106–114 (2003).
   Google Scholar
• Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Ann. Rev. Immunol.22, 531–562 (2004).
   PubMed Web of Science ®Google Scholar
• Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol.8(2), 191–197 (2007).
   PubMed Web of Science ®Google Scholar
• Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F. Regulatory T cells and intestinal homeostasis. Immunol. Rev.204, 184–194 (2005).
   PubMed Web of Science ®Google Scholar
• Bourreau E, Ronet C, Darcissac E et al. Intralesional regulatory T-cell suppressive function during human acute and chronic cutaneous leishmaniasis due to Leishmania guyanensis. Infect. Immun.77(4), 1465–1474 (2009).
   PubMedGoogle Scholar
• Cederbom L, Hall H, Ivars F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol.30(6), 1538–1543 (2000).
   PubMed Web of Science ®Google Scholar
• Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M. Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc. Natl Acad. Sci. USA99(24), 15620–15625 (2002).
   PubMedGoogle Scholar
• Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol.4(4), 330–336 (2003).
   PubMed Web of Science ®Google Scholar
• Hall BM, Pearce NW, Gurley KE, Dorsch SE. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action. J. Exp. Med.171(1), 141–157 (1990).
   PubMed Web of Science ®Google Scholar
• Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science299(5609), 1057–1061 (2003).
   PubMed Web of Science ®Google Scholar
• Fletcher JM, Lonergan R, Costelloe L et al. CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J. Immunol. (Balt.)183(11), 7602–7610 (2009).
   PubMed Web of Science ®Google Scholar
• Kleinewietfeld M, Starke M, Di Mitri D et al. CD49d provides access to ‘untouched’ human Foxp3+ Treg free of contaminating effector cells. Blood113(4), 827–836 (2009).
   PubMed Web of Science ®Google Scholar
• Lee YK, Mukasa R, Hatton RD, Weaver CT. Developmental plasticity of Th17 and Treg cells. Curr. Opin. Immunol.21(3), 274–280 (2009).
   PubMed Web of Science ®Google Scholar
• Khattar M, Chen W, Stepkowski SM. Expanding and converting regulatory T cells: a horizon for immunotherapy. Arch. Immunol. Ther. Exp. (Warsz.)57(3), 199–204 (2009).
   PubMedGoogle Scholar
• Zheng SG, Wang J, Horwitz DA. Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-β are resistant to Th17 conversion by IL-6. J. Immunol. (Balt.)180(11), 7112–7116 (2008).
   PubMed Web of Science ®Google Scholar
• Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-β to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J. Immunol. (Balt.)178(4), 2018–2027 (2007).
   PubMed Web of Science ®Google Scholar
• Johnson J, Pahuja A, Graham M, Hering B, Hancock WW, Bansal-Pakala P. Effects of histone deacetylase inhibitor SAHA on effector and FOXP3+regulatory T cells in rhesus macaques. Transplant. Proc.40(2), 459–461 (2008).
   PubMedGoogle Scholar
• Lucas JL, Mirshahpanah P, Haas-Stapleton E, Asadullah K, Zollner TM, Numerof RP. Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. Cell. Immunol.257(1–2), 97–104 (2009).
   PubMed Web of Science ®Google Scholar
• Saouaf SJ, Li B, Zhang G et al. Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis. Exp. Mol. Pathol.87(2), 99–104 (2009).
   PubMed Web of Science ®Google Scholar
• Tao R, De Zoeten EF, Ozkaynak E et al. Histone deacetylase inhibitors and transplantation. Curr. Opin. Immunol.19(5), 589–595 (2007).
   PubMedGoogle Scholar
• Delgado M, Chorny A, Gonzalez-Rey E, Ganea D. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J. Leukoc. Biol.78(6), 1327–1338 (2005).
   PubMed Web of Science ®Google Scholar
• Gonzalez-Rey E, Chorny A, Fernandez-Martin A, Ganea D, Delgado M. Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood107(9), 3632–3638 (2006).
   PubMed Web of Science ®Google Scholar
• Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Delgado M. Vasoactive intestinal peptide induces CD4+,CD25+ T regulatory cells with therapeutic effect in collagen-induced arthritis. Arthritis Rheum.54(3), 864–876 (2006).
   PubMed Web of Science ®Google Scholar
• Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J. Leukoc. Biol.82(5), 1083–1094 (2007).
   PubMed Web of Science ®Google Scholar
• Benner EJ, Mosley RL, Destache CJ et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc. Natl Acad. Sci. USA101(25), 9435–9440 (2004).
   PubMed Web of Science ®Google Scholar
• Garg SK, Banerjee R, Kipnis J. Neuroprotective immunity: T cell-derived glutamate endows astrocytes with a neuroprotective phenotype. J. Immunol. (Balt.)180(6), 3866–3873 (2008).
   PubMedGoogle Scholar
• Rossi D, Volterra A. Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res. Bull.80(4–5), 224–232 (2009).
   PubMedGoogle Scholar
• Wahl SM, Swisher J, McCartney-Francis N, Chen W. TGF-β: the perpetrator of immune suppression by regulatory T cells and suicidal T cells. J. Leukoc. Biol.76(1), 15–24 (2004).
   PubMed Web of Science ®Google Scholar
• Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med.197(1), 111–119 (2003).
   PubMed Web of Science ®Google Scholar
• Costantino CM, Baecher-Allan CM, Hafler DA. Human regulatory T cells and autoimmunity. Eur. J. Immunol.38(4), 921–924 (2008).
   PubMed Web of Science ®Google Scholar
• Putnam AL, Brusko TM, Lee MR et al. Expansion of human regulatory T-cells from patients with Type 1 diabetes. Diabetes58(3), 652–662 (2009).
   PubMed Web of Science ®Google Scholar
• Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev.223, 371–390 (2008).
   PubMed Web of Science ®Google Scholar
• Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J. Neuroimmunol.216(1–2), 113–117 (2009).
   PubMed Web of Science ®Google Scholar
• Vandenbark AA, Huan J, Agotsch M et al. Interferon-β-1a treatment increases CD56bright natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis. J. Neuroimmunol.215(1–2), 125–128 (2009).
   PubMed Web of Science ®Google Scholar
• Aharoni R, Teitelbaum D, Leitner O, Meshorer A, Sela M, Arnon R. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc. Natl Acad. Sci. USA97(21), 11472–11477 (2000).
   PubMed Web of Science ®Google Scholar
• Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib-Jalbut S. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Mult. Scler.7(4), 209–219 (2001).
   PubMed Web of Science ®Google Scholar
• Aharoni R, Teitelbaum D, Sela M, Arnon R. 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. USA94(20), 10821–10826 (1997).
   PubMed Web of Science ®Google Scholar
• Aharoni R, Eilam R, Stock A et al. Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing–remitting or chronic EAE. J. Neuroimmunol.225(1–2), 100–111 (2010).
   PubMed Web of Science ®Google Scholar
• Laurie C, Reynolds A, Coskun O, Bowman E, Gendelman HE, Mosley RL. CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J. Neuroimmunol.183(1–2), 60–68 (2007).
   PubMed Web of Science ®Google Scholar
• Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate TH17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J. Immunol. (Balt.)184(5), 2261–2271 (2010).
   PubMed Web of Science ®Google Scholar