DNA Immunization Against Amyloid beta 42 has High Potential as Safe Therapy for Alzheimer’s Disease as it Diminishes Antigen-Specific Th1 and Th17 Cell Proliferation
The pathogenesis of Alzheimer’s disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1–3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD.
KeywordsAmyloid beta Alzheimer’s disease Immunotherapy Gene gun Immune response Inflammation Th17
This work was supported by the UTSouthwestern Alzheimer’s Disease Center, NIH/NIA Grant P30AG12300-16, Friends of the ADC Grant 2010, The Rudman Foundation and an Alzheimer’s Association Research Grant IIRG-06-24428.
- Ghochikyan A, Vasilevko V, Petrushina I, Movsesyan N, Babikyan D, Tian W, Sadzikava N, Ross TM, Head E, Cribbs DH, Agadjanyan MG (2003) Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur J Immunol 33(12):3232–3241PubMedCrossRefGoogle Scholar
- Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–982PubMedCrossRefGoogle Scholar
- Kim HD, Tahara K, Maxwell JA, Lalonde R, Fukuiwa T, Fujihashi K, Van Kampen KR, Kong FK, Tang DC, Fukuchi K (2007b) Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Abeta1-6 upregulates IL-10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer’s disease. J Gene Med 9:88–98PubMedCrossRefGoogle Scholar
- Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, Fisher Y, Owens T, Weiner HL (2006) Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 103:5048–5053PubMedCrossRefGoogle Scholar
- Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–985PubMedCrossRefGoogle Scholar
- Movsesyan N, Mkrtichyan M, Petrushina I, Ross TM, Cribbs DH, Agadjanyan MG, Ghochikyan A (2008a) DNA epitope vaccine containing complement component C3d enhances anti-amyloid-beta antibody production and polarizes the immune response towards a Th2 phenotype. J Neuroimmunol 205(1–2):57–63PubMedCrossRefGoogle Scholar
- Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177PubMedCrossRefGoogle Scholar
- Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842PubMedCrossRefGoogle Scholar
- Siffrin V, Radbruch H, Glumm R, Niesner R, Paterka M, Herz J, Leuenberger T, Lehmann SM, Luenstedt S, Rinnenthal JL, Laube G, Luche H, Lehnardt S, Fehling H-J, Griesbeck O, Zipp F (2010) In vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 33(3):424–436PubMedCrossRefGoogle Scholar