Enhancing Th2 immune responses against amyloid protein by a DNA prime-adenovirus boost regimen for Alzheimer's disease

Abstract

Accumulation of aggregated amyloid β-protein (Aβ) in the brain is thought to be the initiating event leading to neurodegenetation and dementia in Alzheimer's disease (AD). Therefore, therapeutic strategies that clear accumulated Aβ and/or prevent Aβ production and its aggregation are predicted to be effective against AD. Immunization of AD mouse models with synthetic Aβ prevented or reduced Aβ load in the brain and ameliorated their memory and learning deficits. The clinical trials of Aβ immunization elicited immune responses in only 20% of AD patients and caused T-lymphocyte meningoencephalitis in 6% of AD patients. In attempting to develop safer vaccines, we previously demonstrated that an adenovirus vector, AdPEDI-(Aβ1-6) 11 , which encodes 11 tandem repeats of Aβ1-6 can induce anti-inflammatory Th2 immune responses in mice. Here, we investigated whether a DNA prime-adenovirus boost regimen could elicit a more robust Th2 response using AdPEDI-(Aβ1-6) 11 and a DNA plasmid encoding the same antigen. All mice (n = 7) subjected to the DNA prime-adenovirus boost regimen were positive for anti-Aβ antibody, while, out of 7 mice immunized with only AdPEDI-(Aβ1-6) 11 , four mice developed anti-Aβ antibody. Anti-Aβ titers were indiscernible in mice (n = 7) vaccinated with only DNA plasmid. The mean anti-Aβ titer induced by the DNA prime-adenovirus boost regimen was approximately 7-fold greater than that by AdPEDI-(Aβ1-6) 11 alone. Furthermore, anti-Aβ antibodies induced by the DNA prime-adenovirus boost regimen were predominantly of the IgG1 isotype. These results indicate that the DNA primeadenovirus boost regimen can enhance Th2-biased responses with AdPEDI-(Aβ1-6) 11 in mice and suggest that heterologous prime-boost strategies may make AD immunotherapy more effective in reducing accumulated Aβ.

The central role of T-cell memory in Alzheimer’s disease vaccination

“…The mean anti-Aβ titer induced by the DNA prime-adenovirus boost regimen was some7-fold greater versus the AdPEDI-(Aβ1-6)11 alone. 53 Further, genetic immunization with the Aβ1-42 gene in AD transgenic mice effectively elicited a humoral immune response without a significant T-cell-mediated immune response to the Aβ peptide. 54 Additionally, papillomavirus-like particles (VLP) have also been employed which display Aβ1-9 protein repetitively on the capsid surface.…”

Immunization Therapy for Alzheimer Disease: A Comprehensive Review of Active Immunization Strategies

“…1) AAV-Aβ 1-43 or 1-21 Oral (Hara et al 2004;Mouri et al 2007) 2) AAV-Aβ 1-42 -CTB Oral (Zhang et al 2003) 3) SeV-Aβ 1-43 -IL-10 Nasal (Hara et al in preparation) 4) pCA-PEDI-11 × (Aβ 1-16) boosted with rAV-PEDI*-11 × (Aβ 1-16) Nasal (Kim et al 2007a(Kim et al , 2007b 5) pHSV-Aβ 1-42-IL-4 S.C. (Frazer et al 2008) AAV, adeno-associated virus vector; AV, adenovirus vector; CTB, cholera toxin B; pCA, a plasmid; pHSV, herpes simplex virus amplicon; SeV, Sendai virus vector; PEDI, receptor binding domain of Pseudomonas exotoxin A.…”

“…Our vaccine carries Aβ 1-43 only and does not require adjuvant. , and then the mice were boosted nasally every 3 seeks for 10 months with recombinant Adenovirus containing the same gene construct (Kim et al 2007a(Kim et al , 2007b. The mice produced high titers of IgG1 and IgG2b antibodies to Aβ and SPs were significantly reduced.…”

Enhanced immune response against HIV-1 induced by a heterologous DNA prime-adenovirus boost vaccination using mannosylated polyethyleneimine as DNA vaccine adjuvant

“…3,[6][7][8] After the efficacy of this approach was first reported by Schneider et al, 9 a number of investigators have demonstrated that the heterologous prime-boost strategy is capable of eliciting greater levels of immunity against a variety of tumors and pathogens than homologous prime-boost strategy or a single vaccination of the same vector. 7,10 Moreover, the heterologous prime-boost regimen using recombinant viral vector in combination with DNA plasmid has the ability to induce Th1 (T helper cells type I) CD4 + responses. 7 As the priming vaccination in the prime-boost regimen (though the DNA plasmid vaccination itself has been proved to be one effective way of inducing antigen-specific Th1 and cytotoxic CD8…”

“…The Th1 response, which induces the IgG2a subtype, is primarily cellular, while the Th2 immune response, which induces the IgG1 subtype, is primarily associated with antibody production. 10 An IgG1:IgG2a ratio # 0.5 indicates a Th1-biased immune response, while a ratio $ 2 indicates a Th2-biased immune response. Ratios between 0.5 and 2 indicate a mixed response.…”