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Chris and Keerstin

Prototype Alzheimer’s Disease Vaccine Using the Immunodominant B Cell Epitope from -Amyloid and Promiscuous T Cell Epitope Pan HLA DR-Binding Peptide1. Chris and Keerstin. Authors.

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Chris and Keerstin

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  1. Prototype Alzheimer’s Disease Vaccine Using theImmunodominant B Cell Epitope from -Amyloid andPromiscuous T Cell Epitope Pan HLA DR-Binding Peptide1 Chris and Keerstin

  2. Authors • Affiliated with Institute for Molecular Medicine: Michael G Agadjanyan, Nina Movsesyan, Anahit Ghochikyan, Mikayel Mkrtichyan • Affiliated with Institute for Brain Aging and Dementia: Irina Petrushina, Vitaly Vasilevko, Tommy Saing, David H Cribbs

  3. Alzheimer’s Disease • Most common form of dementia in the elderly • Symptoms include memory loss and cognitive decline • Estimated 26.6 million people have AD (2006) • Characterized by plaques in the brain

  4. Characterized by plaques on brain tissue • Plaques made of insoluble β-amyloid (Aβ) protein, cleaved from neuron surface protein APP • APP cleavage enzymes known, reason for cleavage is not.

  5. Paper • Aβ used as target for Alzheimer’s immunotherapy. • Mice showed positive results • Aβ deposits blocked • Even established Aβ plaques cleared in older mice • Clinical trials in humans led to meningoencephalitis in 6% of patients • Meningitis and encephalitis • Result of T-cell mediated autoimmune response

  6. Want B-cell response without T-cell reaction • Authors propose vaccine with intact B-cell epitope, but T epitope replaced with a general T-epitope (PADRE). • PADRE spliced together with Aβ segment 1-15 to form a Multiple Antigenic Peptide (MAP) • So… PADRE Aβ 1-15MAP is new proposed vaccine • Purpose of Paper is to test effectiveness of new vaccine

  7. Figure 1: ELISA B-cell proliferation from vaccination with Aβ epitopes shows that vaccine does have desired B-response. Aβ1-15 alone produces NO antibodies

  8. Figure 2: ELISA Different cytokines are responsible for production of different Ab types. What type of Abs are being produced? PADRE Aβ 1-15 vaccine produced far more IgG1 type Abs.

  9. Figure 2: (continued) In PADRE Aβ 1-15 vaccine, a higher percentage of Abs produced were of the IgG1 type. In mice, IgG1 antibodies are induced by Th-2 cytokines. (Th-1 induce IgG2a) Therefore, PADRE Aβ 1-15 vaccine produces antibodies through Th-2 polarized response. Mean

  10. Figure 3: Brain section observing antibody binding to Aβ plaques (in vitro) Aβ 1-15 alone showed no localization (remember: no response to vaccination) Both Aβ1-33MAP and PADRE Aβ1-15MAP did show antibody localization on plaques.

  11. Figure 4. T Cell Proliferation • Previous clinical trial involved unwanted T cell immune responses • Test that T cell responses to vaccine were directed against PADRE • A20-31-MAP did not induce T cell proliferationNo T cell epitope • PADRE-A1-15-MAP induced T cell proliferation after stimulation with PADRE, PADRE-A1-15, and PADRE-A1-15-MAP, but not with A40, or A1-15-MAPPADRE provides T cell immune response

  12. Figure 5. Detection of IL-4, TNF-, and IFN- • A1-33-MAP induced the highest IL-4 and IFN- responses followed by intermediate responses to PADRE-A1-15-MAP • As expected, A1-15 did not induce a response • Suggests that these vaccines induce a Th2 polarized immune response in H-2d haplotype mice • A Th2 polarized response results in the production of antibodies and reduces the chance of adverse T cell mediated immune response

  13. Figure 6. Expression of IL-18R and T1/ST2-specific markers on CD4+ T cells • Analyzed percentage of CD4+ T cells expressing either Th1(IL-18R) or Th2 (T1/ST2)-specific markers to further characterize Th1 and Th2 contributions • After in vitro activation and restimulation with A1-33-MAP, they found that PADRE-A1-15-MAP generated 18-19% CD4+ T cells that expressed T1/ST2 molecules after day 7. • The vaccines induced low levels of IL-18R. This further shows that their vaccine, PADRE-A1-15-MAP, induces a Th2-polarized immune response.

  14. Discussion • Many strategies for AD immunotherapy involve blocking the assembly -amyloid peptide • Vaccine that would target the immunogenic B cell epitope of A • Limit an adverse T cell mediated immune response • Mice immunized with PADRE-A1-15-MAP and A1-15-MAP bound equally well to A plaques, suggesting they may be therapeutic • PADRE was shown to produce antibodies against the A peptide • PADRE-A1-15-MAP epitope vaccine induces a highly Th2 polarized immune response • PADRE, not A or MAP peptides, induce T cell responses, which means that the PADRE provides the T cell support for a strong anti-A antibody response to the vaccine

  15. Questions?

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