Journal
CELLULAR AND MOLECULAR NEUROBIOLOGY
Volume 31, Issue 6, Pages 867-874Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10571-011-9680-7
Keywords
Amyloid beta; Alzheimer's disease; Immunotherapy; Gene gun; Immune response; Inflammation; Th17
Categories
Funding
- UTSouthwestern Alzheimer's Disease Center
- NIH/NIA [P30AG12300-16]
- ADC
- Rudman Foundation
- Alzheimer's Association [IIRG-06-24428]
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The pathogenesis of Alzheimer's disease (AD) has been strongly associated with the accumulation of amyloid beta (A beta) peptides in brain, and immunotherapy targeting A beta provides potential for AD prevention. A clinical trial in which AD patients were immunized with A beta 42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that A beta 42 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 A beta 42 peptide re-stimulation was absent in DNA A beta 42 trimer-immunized mice when compared to A beta 42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wildtype mice after vaccination with A beta 42 trimer DNA and A beta 42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1-3x vaccinations) or long-term (6x vacinations) immunization strategies. Antibody titers and isotype profiles of the A beta 42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce A beta 42, but an absent T cell proliferative response and no IFN gamma or IL-17 secretion after A beta 42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen A beta 42 in brain. Therefore, A beta 42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD.
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