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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

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Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9036, USA

    Doris Lambracht-Washington, Bao-Xi Qu, Min Fu, Olaf Stüve, Todd N. Eagar & Roger N. Rosenberg

  2. Alzheimer’s Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Doris Lambracht-Washington, Bao-Xi Qu, Min Fu & Roger N. Rosenberg

  3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Larry D. Anderson Jr

  4. VA North Texas Health Care System, Medical Service Dallas VA Medical Center, Dallas, TX, USA

    Olaf Stüve

  5. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Todd N. Eagar

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  1. Doris Lambracht-Washington
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  2. Bao-Xi Qu
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  3. Min Fu
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  4. Larry D. Anderson Jr
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  5. Olaf Stüve
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  6. Todd N. Eagar
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  7. Roger N. Rosenberg
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Correspondence to Roger N. Rosenberg.

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Todd N. Eagar and Roger N. Rosenberg are Senior Authors for this Publication

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Lambracht-Washington, D., Qu, BX., Fu, M. et al. 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. Cell Mol Neurobiol 31, 867–874 (2011). https://doi.org/10.1007/s10571-011-9680-7

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  • DOI: https://doi.org/10.1007/s10571-011-9680-7

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