P2‐470: T cell responses after DNA Abeta‐42 trimer immunization in mice indicate the potential for safe immunotherapy for Alzheimer's disease
Year: 2011
Type: article
Abstract: Pathogenesis of Alzheimer's disease (AD) has been strongly associated with the accumulation and deposition of amyloid beta (Abeta) peptides in brain, and immunotherapy targeting Abeta42 provides potential for AD prevention. A clinical trial in which early AD patients were immunized with Abeta42 peptide was stopped when 6% of participant showed signs of meningoencephalitis due to an inflammatory Th1 immune response. The finding of Th2 immune responses following DNA vaccination via gene gun has been shown in several studies including ours by analyses of the respective antibody isotype profiles. However, we found also that a specific T cell response to Abeta42 was missing in DNA Abeta42 trimer immunized mice when compared to Abeta42 peptide immunized mice (1). To analyze in detail what happens over time we analyzed now the immune response in wild-type mice after vaccination with Abeta42 trimer DNA and Abeta42 peptide in a longitudinal study. Wild-type mice were immunized with DNA Abeta42 trimer delivered by gene gun or Abeta42 peptide with Quil A adjuvant via i.p. injections for short (1-3x) or extended immunization (6-8x) periods. In both groups, the Abeta42 antibody titers increased with continued immunization times. The antibody isotypes in the DNA immunized mice switched to IgG1 after the 3 immunization indicating Th2 T cell help had occurred. Abeta42 specific T cell proliferation and Abeta42 specific T cell precursor frequencies as well as cytokine levels in antigen re-stimulated cell cultures decreased with continued DNA immunization time points which might be indicative of a regulatory mechanism involved in this particular model. Sufficient antibody titers to be effective for plaque removal but a missing T cell response after Abeta42 DNA trimer immunization reduces the risk of inflammatory activities of the immune system towards the self antigen Abeta42 in brain. Therefore, Abeta42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD. (1) Lambracht-Washington D, Qu B-X, Fu M, Eagar TN, Stüve O, Rosenberg RN DNA ß-Amyloid1-42 Trimer Immunization for Alzheimer Disease in a Wild-Type Mouse Model. JAMA 2009; 302(16):1796-1802.
Source: Alzheimer s & Dementia
Authors: Doris Lambracht‐Washington, Bao‐Xi Qu, Min Fu, Todd N. Eagar, Olaf Stuve, Roger N. Rosenberg
Institution: The University of Texas Southwestern Medical Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2042436758