Virus and virus-like particle-based immunogens for Alzheimer's disease induce antibody responses against amyloid-β without concomitant T cell responses

Chackerian, Bryce; Rangel, Marisa; Hunter, Zoe; Peabody, David S.

doi:10.1016/j.vaccine.2006.05.059

Cited by 108 publications

(88 citation statements)

References 59 publications

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“…However, adjuvants that potently stimulate innate immune responses may have unwanted effects in humans-even if considered safe in mouse models (10 -12, 14, 53). Alternatively, A␤ display via Escherichia coli filamentous or Q␤ phage (47,54,55) and A␤ presented on the surface of nonenveloped papilloma VLPs has been used (52, 55) as immunogens. Zamora et al (51) fused A␤1-9 to the major capsid protein L1 of Bovine papilloma virus.…”

Section: Discussionmentioning

confidence: 99%

“…Although these A␤1-9 VLP presented A␤ at a rather high density (360 copies per particle) and evoked Abs that inhibited fibril formation in vitro, no significant reduction of plaque burden or cerebral A␤ levels were obtained in vaccinated APP transgenic mice (51). Another study used papilloma VLP or Q␤ phage that carried cross-linked A␤ epitopes of variable length (54). Interestingly, this led to high Ab titers (comparable to A␤1-42/CFA immunization) and Th cell responses that were predominantly directed against VLP epitopes.…”

Section: Discussionmentioning

confidence: 99%

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Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Bach

Tschäpe

Kopietz

et al. 2009

The Journal of Immunology

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In transgenic animal models, humoral immunity directed against the β-amyloid peptide (Aβ), which is deposited in the brains of AD patients, can reduce Aβ plaques and restore memory. However, initial clinical trials using active immunization with Aβ1–42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Aβ. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Aβ (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Aβ retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Aβ retroparticles evoked high and long-lived Aβ-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Aβ plaque load to ∼60% of controls and lowered both insoluble Aβ40 as well as Aβ42 in APP23 brain, but also significantly reduced cerebral soluble Aβ species. In summary, Aβ retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Bach

Tschäpe

Kopietz

et al. 2009

The Journal of Immunology

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“…To determine whether VLP conjugation could induce anti-HEL autoantibodies in the well-characterized HEL mouse model of B cell tolerance, we first generated a multivalent Ag in which HEL was conjugated at high density to the surface of VLPs. These HELconjugated VLPs were generated using the SA-bridge approach, which we have previously shown results in high-density coating of VLPs with target Ag (24). Biotinylated HEL was reacted with SA at a molar ratio that leaves, on average, at least one of the four biotin-binding sites on the SA tetramer unoccupied.…”

Section: Hel-conjugated Vlps Bind To the Tg Hel-specific Bcrmentioning

confidence: 99%

Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

Chackerian

Durfee

Schiller

2008

The Journal of Immunology

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The ability to distinguish between self and foreign Ags is a central feature of immune recognition. For B cells, however, immune tolerance is not absolute, and factors that include Ag valency, the availability of T help, and polyclonal B cell stimuli can influence the induction of autoantibody responses. Here, we evaluated whether multivalent virus-like particle (VLP)-based immunogens could induce autoantibody responses in well-characterized transgenic (Tg) mice that express a soluble form of hen egg lysozyme (HEL) and in which B cell tolerance to HEL is maintained by anergy. Immunization with multivalent VLP-arrayed HEL, but not a trivalent form of HEL, induced high-titer Ab responses against HEL in both soluble HEL Tg mice and double Tg mice that also express a monoclonal HEL-specific BCR. Induction of autoantibodies against HEL was not dependent on coadministration of strong adjuvants, such as CFA. In contrast to previous data showing the T-independent induction of Abs to foreign epitopes on VLPs, the ability of HEL-conjugated VLPs to induce anti-HEL Abs in tolerant mice was dependent on the presence of CD4+ Th cells, and could be enhanced by the presence of pre-existing cognate T cells. In in vitro studies, VLP-conjugated HEL was more potent than trivalent HEL in up-regulating surface activation markers on purified anergic B cells. Moreover, immunization with VLP-HEL reversed B cell anergy in vivo in an adoptive transfer model. Thus, Ag multivalency and T help cooperate to reverse B cell anergy, a major mechanism of B cell tolerance.

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“…Rabbit and mouse vaccinations were well tolerated and induced high-titer antibody against Aβ, that effectively inhibited assembly of Aβ1-42 peptides into neurotoxic fibrils in vitro. 55 In PSAPP mice trends for reduced brain Aβ deposits, and increased Aβ in plasma, suggested efflux from the brain to periphery as well. 51,52 These results are important because the Th2 response is salutary in the CNS in AD.…”

Section: Animal Aβ Immunizationmentioning

confidence: 99%

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

Giunta¹,

Ruscin²,

Salemi³

et al. 2010

Ageing Res

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Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disease as well as the most common dementia among the elderly. In the future as the average lifespan continues to extend, the number of AD patients will continue to grow. Amyloidbeta (Aβ) peptides, in both soluble oligomeric, and insoluble forms, are key in the neuropathogenesis of AD and have thus been a therapeutic target for vaccines. Multiple Aβ vaccination strategies in animal models of AD have demonstrated a marked reduction in both amyloid burden and neurocognitive deficits. Due to the success of these studies, initial human clinical trials of an active Aβ vaccine were conducted. These were discontinued due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Studies examining the brains of Aβ-vaccinated patients developing meningoencephalitis implicate Aβ-reactive T-cell subsets as major components of this deleterious response to active Aβ vaccination. To subvert possible meningoencephalitis resulting from Aβ vaccination a second generation of vaccines has been more recently developed. These however have met with little success in humans. To build on these findings, an understanding of the role of T-cells in vaccination against Aβ is presented in this review. Various methods of Aβ immunotherapy are reviewed including studies in both animal models and humans. Recent works suggest that Aβ-derived peptides delivered intranasally or transcutaneously results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD. Moreover, undesired T-cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In spite of the past clinical studies, these findings imply that Aβ vaccination may be both efficacious and safe depending route of delivery, adjuvant choice, and Aβ epitope administered.

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Virus and virus-like particle-based immunogens for Alzheimer's disease induce antibody responses against amyloid-β without concomitant T cell responses

Cited by 108 publications

References 59 publications

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

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

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