Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

Ghochikyan, Anahit; Mkrtichyan, Mikayel; Petrushina, Irina; Movsesyan, Nina; Karapetyan, Adrine; Cribbs, David H.; Agadjanyan, Michael G.

doi:10.1016/j.vaccine.2005.11.039

Cited by 78 publications

(71 citation statements)

References 51 publications

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“…2A, mean anti-A␤ antibody levels elicited by Trx(A␤15) 4 and Trx(A␤15) 8 (but not monomeric TrxA␤15) were significantly higher (p Յ 0.05) than those of mock-treated controls and similar to those of the A␤42-treated groups, where TrxA␤42 performed as well as free A␤42. An anti-inflammatory T helper 2-polarized response, typical of the alum adjuvant (14,25,53), was revealed by isotype profiling (Fig. 2B).…”

Section: Design and Construction Of The Trx(a␤15) N Polypeptides-mentioning

confidence: 96%

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

Moretto

Bolchi

Rivetti

et al. 2007

Journal of Biological Chemistry

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Immunotherapy against the amyloid-␤ (A␤) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of A␤, and yet be capable of eliciting antibodies that recognize A␤ fibrils and neurotoxic A␤ oligomers but not the physiological monomeric species of A␤. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide A␤1-15 (A␤15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(A␤15) n polypeptides bearing one, four, or eight copies of A␤15 were constructed and injected into mice in combination with alum, an adjuvant approved for human use. All three polypeptides were found to be immunogenic, yet eliciting antibodies with distinct recognition specificities. The anti-Trx(A␤15) 4 antibody, in particular, recognized A␤42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to A␤. We have also demonstrated that anti-Trx(A␤15) 4 , which binds to human AD plaques, markedly reduces A␤ pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained A␤ fragment repeat and identify Trx(A␤15) 4 as a promising new tool for AD immunotherapy.Antipeptide antibodies are valuable tools for probing structure-function relationships in proteins as well as for therapeutic and diagnostic applications. When immunotherapy is the ultimate goal, the sequence span of the peptide, and thus the nature of the epitope(s) associated with it, as well as the conformational selectivity of the resulting antibodies may also be dictated by safety reasons. This is the case of the amyloid-␤ (A␤) 2 peptide, a major neuropathological hallmark (1-3) and a promising immunotherapeutic target of Alzheimer disease (AD) (4 -7). Following the encouraging results obtained with A␤42 vaccination in transgenic mouse models of AD (8 -10), a Phase II clinical trial utilizing preaggregated A␤42 as an antigen and the QS-21 saponin as an immunoadjuvant (AN-1792 vaccine) was halted due to the occurrence of meningoencephalitis in ϳ6% of treated patients (11-13). T-cell-mediated autoimmunity produced by the C-terminal portion of A␤ (14) along with a predominantly pro-inflammatory (T helper 1) immunoresponse and cross-reactivity with the presumably physiological monomeric forms of A␤ (A␤38 -43 peptides plus the amyloid-␤ precursor protein have been hypothesized as the main causes of these adverse effects (15-17). Of further concern is the fact that not only plaques but also soluble A␤ oligomers should be bound by a therapeutically effective antibody (18 -20). The latter represent an intermediate conformation prior to fibril formation and are presently considered as the most proximate causative agents of . S...

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Section: Design and Construction Of The Trx(a␤15) N Polypeptides-mentioning

confidence: 96%

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

Moretto

Bolchi

Rivetti

et al. 2007

Journal of Biological Chemistry

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“…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%

“…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.…”

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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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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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“…The Th2 cytokine profile is likely favorable for inducing antibody production and thus A␤ clearance without the overt proinflammatory (i.e., possibly contributing to autoimmune responses) Th1-type activation that typifies cellular immune responses (19,36,37). Accordingly, to circumvent meningoencephalitic reactions, many studies investigating vaccination methods for reducing cerebral amyloidosis in AD have attempted to bias Th cell responses toward Th2 profiles by using various strategies (38)(39)(40). The effectiveness and potential safety of these strategies seems promising, but further investigation is needed to confirm whether the link between Th cell responses and meningoencephalitis in AD patients is causative.…”

Section: Discussionmentioning

confidence: 99%

Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

Nikolic¹,

Bai²,

Obregon³

et al. 2007

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

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This therapeutic approach is clearly highly efficacious; however, the safety of this strategy has become an important concern. In a recent clinical trial, patients were administered a synthetic A␤ peptide (AN-1792) plus adjuvant, and Ϸ6% of these patients developed aseptic meningoencephalitis, most likely mediated by braininfiltrating activated T cells (3,4). This serious side effect led to suspension of the clinical trial. Furthermore, passive transfer of A␤ antibodies to transgenic AD mice results in cerebral microhemorrhage, a potentially adverse side effect (5, 6). Uncovering of these adverse events has redirected A␤ vaccination strategies toward the goal of developing an approach that is both safe and effective.Studies examining the brains of A␤-vaccinated patients developing meningoencephalitis implicate A␤-reactive T cell subsets as major components of this deleterious response to active A␤ vaccination (7, 8). To subvert possible meningoencephalitis resulting from A␤ vaccination, various strategies have been attempted. Interestingly, recent works suggest that A␤-derived peptides delivered intranasally (with adjuvant) to mucosal epithelial tissues results in effective clearance of A␤ plaques and improvement of cognitive function in animal models of AD. Moreover, T cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In other studies, differential T cell responses depended on the epitope/fragment of A␤ peptide used for vaccination. Specifically, portions of the A␤ peptide seemed to stimulate different T cell responses, resulting in either proinflammatory T helper (Th) cell type 1 (Th1) responses or antiinflammatory Th cell type 2 (Th2) responses (9, 10). Such findings imply that A␤ vaccination is not only efficacious, but may also prove to be safe and therefore a feasible strategy for AD therapy depending on a number of factors, including route of delivery, adjuvant choice, and A␤ epitope administered.The skin is a well established effective route for vaccination, including delivery of peptide-based vaccines (11-13). Strong humoral and cellular immune responses have been elicited after transcutaneous (t.c.) vaccination (14), largely owing to the diverse populations of resident antigen-presenting cells (APCs) and other immune cells in the various dermal layers. Subsets of dermalresident Langerhans cell (LC) precursors, known as migratory CD14 ϩ LC precursors, are important immune regulators that demonstrate ''professional'' APC capability, including reducing T cell stimulatory function by producing antiinflammatory cytokines (15). Also, skin-resident keratinocytes release the antiinflammatory cytokine IL-10 in response to certain stimuli. Keratinocytederived IL-10 serves to buffer harmful proinflammatory immune activation and thereby preserves skin barrier integrity (16).Taken together, these lines of evidence led us to hypothesize that targeting A␤ immunotherapy to skin tissue might provide an immunotherapeutic approach that is both efficacious and safe. In...

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Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

Cited by 78 publications

References 51 publications

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

Conformation-sensitive Antibodies against Alzheimer Amyloid-β by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide

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

Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

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