Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy.
BACKGROUND
The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Abeta(42) (Abeta(1-11)) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype.


RESULTS
We generated pMDC-3Abeta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Abeta antibody, which in turn inhibited accumulation of Abeta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.


CONCLUSIONS
Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials.
Movsesyan
Nina
N
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, California, United States of America.
Ghochikyan
Anahit
A
Mkrtichyan
Mikayel
M
Petrushina
Irina
I
Davtyan
Hayk
H
Olkhanud
Purevdorj B
PB
Head
Elizabeth
E
Biragyn
Arya
A
Cribbs
David H
DH
Agadjanyan
Michael G
MG
D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D000939:Epitopes / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D017780:Malaria Vaccines / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*
D000939:Epitopes; D017780:Malaria Vaccines; C401223:PADRE 45; D019444:Vaccines, DNA