Abstract
Immunization of amyloid precursor protein transgenic mice with fibrillar beta-amyloid (Abeta) prevents Alzheimer's disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Abeta, containing the B and T cell self epitopes of Abeta, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-Abeta Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Abeta immunotherapy we have designed a prototype epitope vaccine that contains the immunodominant B cell epitope of Abeta in tandem with the synthetic universal Th cell pan HLA DR epitope, pan HLA DR-binding peptide (PADRE). Importantly, the PADRE-Abeta(1-15) sequence lacks the T cell epitope of Abeta. Immunization of BALB/c mice with the PADRE-Abeta(1-15) epitope vaccine produced high titers of anti-Abeta Abs. Splenocytes from immunized mice showed robust T cell stimulation in response to peptides containing PADRE. However, splenocytes from immunized mice were not reactivated by the Abeta peptide. New preclinical trials in amyloid precursor protein transgenic mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse events that occurred in the first clinical trial.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / immunology
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Alzheimer Disease / therapy*
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Alzheimer Vaccines / administration & dosage
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Alzheimer Vaccines / immunology*
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Alzheimer Vaccines / therapeutic use
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Amyloid beta-Peptides / administration & dosage
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Amyloid beta-Peptides / immunology*
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Amyloid beta-Peptides / therapeutic use
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Animals
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Biomarkers
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Epitopes, B-Lymphocyte / administration & dosage
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Epitopes, B-Lymphocyte / immunology*
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Epitopes, B-Lymphocyte / therapeutic use
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Epitopes, T-Lymphocyte / administration & dosage
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Epitopes, T-Lymphocyte / immunology*
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Epitopes, T-Lymphocyte / metabolism
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Epitopes, T-Lymphocyte / therapeutic use
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Female
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HLA-DR Antigens / metabolism*
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Humans
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Immunodominant Epitopes / administration & dosage
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Immunodominant Epitopes / immunology*
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Immunodominant Epitopes / therapeutic use
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Immunoglobulin G / biosynthesis
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Immunoglobulin G / blood
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Immunoglobulin M / biosynthesis
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Immunoglobulin M / blood
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Interleukin-18 Receptor alpha Subunit
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Lymphokines / biosynthesis
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Malaria Vaccines / immunology*
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Malaria Vaccines / metabolism
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Malaria Vaccines / therapeutic use
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Mice
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Mice, Inbred BALB C
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology*
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Peptide Fragments / therapeutic use
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Protein Binding / immunology
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin-18
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / immunology
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Th2 Cells / metabolism
Substances
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Alzheimer Vaccines
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Amyloid beta-Peptides
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Biomarkers
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Epitopes, B-Lymphocyte
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Epitopes, T-Lymphocyte
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HLA-DR Antigens
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IL18R1 protein, human
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Il18r1 protein, mouse
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Immunodominant Epitopes
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Immunoglobulin G
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Immunoglobulin M
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Interleukin-18 Receptor alpha Subunit
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Lymphokines
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Malaria Vaccines
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PADRE 45
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Peptide Fragments
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Receptors, Interleukin
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Receptors, Interleukin-18
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amyloid beta-protein (1-15)
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amyloid beta-protein (1-34)