DNA prime–protein boost increased the titer, avidity and persistence of anti-Aβ antibodies in wild-type mice

Davtyan, Hayk; Mkrtichyan, Mikayel; Movsesyan, Nina; Petrushina, Irina; Mamikonyan, Grigor; Cribbs, David H.; Agadjanyan, Michael G.; Ghochikyan, Anahit

doi:10.1038/gt.2009.140

Cited by 37 publications

(65 citation statements)

References 75 publications

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“…The various EV designs all induced high levels of anti-Ab antibodies without activation of potentially harmful autoreactive Th cells in mice, rabbits, and monkeys. 40,[65][66][67][68] Importantly, immunizations of mouse models of AD with EV induced therapeutically potent antiAb antibodies that inhibited accumulation of AD-like plaque pathology in the brains of older mice, reduced glial activation, and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. 40,42,43 In this study, we decided to compare the efficacy of our EV strategy in preventive and therapeutic settings in parallel.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

et al. 2017

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Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal b-amyloid (Ab 42 ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Ab 42 is a target. Here, we directly compare the efficacy of anti-Ab 42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Ab antibodies, significantly reducing pathologic forms of Ab in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Ab antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance. INTRODUCTIONA critical goal of developing therapeutic interventions for Alzheimer's disease (AD) has been the identification of suitable targets. During the last two decades, the predominant theory of the etiology of AD was that Ab has a central role in the onset and progression of AD, as delineated in the amyloid cascade hypothesis. 1,2 According to this hypothesis, the accumulation of Ab peptide, either by overproduction or aberrant clearance, results in deposition of Ab in plaques, which leads to the formation of neurofibrillary tau tangles and cell death, resulting in dementia. Later on, the amyloid cascade hypothesis evolved to focus on oligomers and protofibrils of Ab as instigators in the destruction of synaptic function. [3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD 6-8 or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques. Importantly, substantial data suggest that Ab pathology emerges many years prior to tau pathology and accelerates formation of toxic tau aggregates, [16][17][18] supporting the preventive rather than therapeutic potential of anti-amyloid therapies.Immunotherapies target...

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Section: Discussionmentioning

confidence: 99%

“…40,43,65,66 Anti-Ab antibody concentrations in mice were calculated using a calibration curve generated with 6E10 monoclonal antibody (Covance).…”

Section: Experimental Set IImentioning

confidence: 99%

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

et al. 2017

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“…WT-5xfAD Mice Lack Aβ-Specific B Cells and Anti-Aβ IgGs. To determine whether these endogenous IgGs were directed against Aβ, we collected sera from WT-WT, WT-5xfAD, and Rag5xfAD mice and measured anti-Aβ antibody titers using a wellvalidated ELISA (34,35). Despite testing extremely undiluted samples of sera, we found no differences between WT-WT and WT-5xfAD in levels of anti-Aβ IgG antibodies (Fig.…”

Section: Microglial Activation and Phagocytosis Is Altered In Rag-5xfadmentioning

confidence: 90%

“…Blood was collected from retroorbital sinus, and titers of anti-Aβ antibodies in mouse sera were determined by ELISA as previously described (34,35). Spleens, deep cervical lymph nodes (DCLNs), and superficial cervical lymph nodes (SCLNs) were collected, and antibody-forming B cells specific to Aβ were detected in splenocytes and pooled DCLN/SCLN lymphocytes by ELISPOT (Mabtech).…”

Section: Methodsmentioning

confidence: 99%

“…Splenocytes or lymphocytes were incubated for 24 h in 96-well plates coated with Aβ peptide, and the assay was performed following manufacturer's protocol (Mabtech). Sera and splenocytes were also collected from mice immunized with Aβ as a positive control (34,35). Analysis of IFNγ production by T cells was performed in DCLN/SCLN lymphocytes by ELISpot assay (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

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The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

337

287

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The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

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DNA vaccination strategies for anti-tumour effective gene therapy protocols

Signori

Iurescia

Massi

et al. 2010

Cancer Immunol Immunother

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After more than 15 years of experimentation, DNA vaccines have become a promising perspective for tumour diseases, and animal models are widely used to study the biological features of human cancer progression and to test the efficacy of vaccination protocols. In recent years, immunisation with naked plasmid DNA encoding tumour-associated antigens or tumour-specific antigens has revealed a number of advantages: antigen-specific DNA vaccination stimulates both cellular and humoral immune responses; multiple or multi-gene vectors encoding several antigens/determinants and immune-modulatory molecules can be delivered as single administration; DNA vaccination does not induce autoimmune disease in normal animals; DNA vaccines based on plasmid vectors can be produced and tested rapidly and economically. However, DNA vaccines have shown low immunogenicity when tested in human clinical trials, and compared with traditional vaccines, they induce weak immune responses. Therefore, the improvement of vaccine efficacy has become a critical goal in the development of effective DNA vaccination protocols for anti-tumour therapy. Several strategies are taken into account for improving the DNA vaccination efficacy, such as antigen optimisation, use of adjuvants and delivery systems like electroporation, co-expression of cytokines and co-stimulatory molecules in the same vector, different vaccination protocols. In this review we discuss how the combination of these approaches may contribute to the development of more effective DNA vaccination protocols for the therapy of lymphoma in a mouse model.

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DNA prime–protein boost increased the titer, avidity and persistence of anti-Aβ antibodies in wild-type mice

Cited by 37 publications

References 75 publications

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

DNA vaccination strategies for anti-tumour effective gene therapy protocols

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