Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene.
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.
Ghochikyan
Anahit
A
The Institute for Molecular Medicine, Department of Immunology, Huntington Beach, USA.
Vasilevko
Vitaly
V
Petrushina
Irina
I
Movsesyan
Nina
N
Babikyan
Davit
D
Tian
Wenqiang
W
Sadzikava
Nadya
N
Ross
Ted M
TM
Head
Elizabeth
E
Cribbs
David H
DH
Agadjanyan
Michael G
MG
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D019470:Biolistics; D016466:CHO Cells; D006224:Cricetinae; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte; D005260:Female; D007114:Immunization; D007132:Immunoglobulin Isotypes / Q000097:blood; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*
D016229:Amyloid beta-Peptides; D018985:Epitopes, B-Lymphocyte; D007132:Immunoglobulin Isotypes; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D015847:Interleukin-4