Co-immunization with DNA and protein mixture: A safe and efficacious immunotherapeutic strategy for Alzheimer's disease in PDAPP mice

Abstract

Active immunotherapy targeting β-amyloid (Aβ) is the most promising strategy to prevent or treat Alzheimer's disease (AD). Based on pre-clinical studies and clinical trials, a safe and effective AD vaccine requires a delicate balance between providing therapeutically adequate anti-Aβ antibodies and eliminating or suppressing unwanted adverse T cell-mediated inflammatory reactions. We describe here the immunological characterization and protective efficacy of co-immunization with a 6Aβ15-T DNA and protein mixture without adjuvant as an AD immunotherapeutic strategy. Impressively, this co-immunization induced robust Th2-polarized Aβ-specific antibodies while simultaneously suppressed unwanted inflammatory T cell reactions and avoiding Aβ42-specific T cell-mediated autoimmune responses in immunized mice. Co-immunization with the DNA + protein vaccine could overcome Aβ42-associated hypo-responsiveness and elicit long-term Aβ-specific antibody responses, which helped to maintain antibody-mediated clearance of amyloid and accordingly alleviated AD symptoms in co-immunized PDAPP mice. Our DNA and protein combined vaccine, which could induce an anti-inflammatory Th2 immune response with high level Aβ-specific antibodies and low level IFN-γ production, also demonstrated the capacity to inhibit amyloid accumulation and prevent cognitive dysfunction. Hence, co-immunization with antigen-matched DNA and protein may represent a novel and efficacious strategy for AD immunotherapy to eliminate T cell inflammatory reactions while retaining high level antibody responses.

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…ACI-24 also improved novel object recognition without triggering proinflammatory responses [73]. Finally, DNA vaccines against Aβ1-42 [98,99], alone or in combination with protein antigens [100,101], have shown promising results at the preclinical stage. DNA-based vaccination utilizes direct injection of DNA-encoding genes for protein or peptide antigens, and it does not require the use of adjuvants.…”

“…DNA-based vaccination utilizes direct injection of DNA-encoding genes for protein or peptide antigens, and it does not require the use of adjuvants. Coimmunization with a mixture of Aβ1-42 DNA and protein is capable of inducing Th2-type Aβ-specific antibodies while simultaneously suppressing unwanted inflammatory reactions and avoiding T-cell-mediated autoimmune responses [100].…”

T Cells—Protective or Pathogenic in Alzheimer’s Disease?

“…Whether this particular method of immunization is protective in transgenic AD-models remains to be determined, however the induction of a non-inflammatory, Th2/Treg type response was encouraging. Indeed Liu and colleagues have demonstrated that coimmunization with Aβ 1-15 DNA and Aβ 1-15 peptide induced Aβ-specific Th2 responses, resulting in improved spatial memory and reduced plaque deposition in PDAPP mice (Liu et al 2015). Together these results suggest that an antiinflammatory immunotherapy may be a more sensible treatment for this disease.…”

Alzheimer's disease vaccine development: A new strategy focusing on immune modulation

“…The Th2-biased response induced by the immunogen expressed in DNA vaccinated mice yielded anti-Aβ antibodies, which reduced the brain's burden for that protein without inflammation. This immunoresponse was increased by either priming with the peptide immunogen followed by genetic vaccination (Lambracht-Washington and Rosenberg, 2012), or by co-immunization with DNA and Aβ mixtures (Liu et al, 2015). Of relevance for AD protection is that in different animal species, DNA vaccination induces antibodies directed to linear Aβ, as well as its relevant conformational epitopes and toxic oligomers (Matsumoto et al, 2013).…”