Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene

Eur J Immunol. 2003 Dec;33(12):3232-41. doi: 10.1002/eji.200324000.

Abstract

Active immunization with fibrillar beta-amyloid peptide (Abeta(42)) as well as passive transfer of anti-Abeta antibodies significantly reduces Abeta plaque deposition, neuritic dystrophy, and astrogliosis in the brain of mutant amyloid precursor protein (APP)-transgenic mice. Although the mechanism(s) of clearance of Abeta from the brain following active or passive immunization remains to be determined, it is clear that anti-Abeta antibodies are critical for clearance. DNA immunization provides an attractive alternative to direct peptide and adjuvant approaches for inducing a humoral response to Abeta. We constructed a DNA minigene with Abeta fused to mouse interleukin-4 (pAbeta(42)-IL-4) as a molecular adjuvant to generate anti-Abeta antibodies and enhance the Th2-type of immune responses. Gene gun immunizations induced primarily IgG1 and IgG2b anti-Abeta antibodies. Fine epitope analysis with overlapping peptides of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The DNA minigene-induced anti-Abeta antibodies bound to Abeta plaques in brain tissue from an Alzheimer's disease patient demonstrating functional activity of the antibodies and the potential for therapeutic efficacy.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / immunology*
  • Animals
  • Biolistics
  • CHO Cells
  • Cricetinae
  • Epitope Mapping
  • Epitopes, B-Lymphocyte
  • Female
  • Immunization
  • Immunoglobulin Isotypes / blood
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Mice
  • Recombinant Fusion Proteins / immunology*
  • Vaccines, DNA / immunology*

Substances

  • Amyloid beta-Peptides
  • Epitopes, B-Lymphocyte
  • Immunoglobulin Isotypes
  • Recombinant Fusion Proteins
  • Vaccines, DNA
  • Interleukin-4