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Review
, 5, 57-68
eCollection

Prion Diseases: Immunotargets and Therapy

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Review

Prion Diseases: Immunotargets and Therapy

Jennifer T Burchell et al. Immunotargets Ther.

Abstract

Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP(Sc) conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4(+) cells to initiate an immune response. Adoptive transfer of CD4(+) T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion diseases.

Keywords: Alzheimer disease; PrPC; PrPSc; dendritice cells; immunization; neurodegeneration; spongiform encephalopathies; tans-missible spongiform encephalopathies Creutzfeldt-Jacob disease.

Figures

Figure 1
Figure 1
Proposed mechanisms of conversion of the prion protein. Notes: (A) The physiological prion protein PrPc is composed mainly of alpha helices. It can convert to an intermediate form PrPInt or a pathological form PrPSc, composed mainly of beta sheets. There are many different intermediate forms, but only one is represented here for clarity. (B) Template-directed refolding proposes that PrPc can convert to PrPInt and then to PrPSc in the presence of a single PrPSc protein. (C) Nucleated polymerization proposes that a PrPc to PrPInt change is reversible; however, the PrPInt to PrPSc change can only occur in the presence of PrPSc oligomers.
Figure 2
Figure 2
Immunology of antibody vaccines. Notes: The PrPSc/antibody complex is too large to intercalate. (A) A mutation in the PRNP gene disrupts two hydrogen bonds between the second β-sheet and second α-helix exposing the SNP6 binding site and enabling the more flexible protein to interact with the receptor. (B) The PrPSc/antibody complex it too large to intercalate with the receptor. Abbreviation: SNP6, single-nucleotide polymorphism 6.
Figure 3
Figure 3
DC and naive T-cell interactions produce an adaptive immune response. Notes: There are three signals required to initiate an adaptive immune response. The first is the presentation of antigen by the DCs to the T-cell via the MHC II–TCR interaction. Second, costimulatory molecules on the DCs such as CD40, CD80, and CD86 bind to their respective receptors on the T-cell to amplify the signal. Third, cytokines produced by the now activated T-cell skew the T-cell response toward a TH1, TH2, Treg, or TH17 response. Abbreviations: DC, dendritic cell; IL-4, interleukin 4; IL-6, interleukin 6; IL-12, interleukin 12; MHCII, major histocompatibility complex class II; TCR, T-cell receptor; TGFβ, transforming growth factor beta; Treg, T regulatory cells; TH1, T helper 1; TH2, T helper 2; TH17, T helper 17.
Figure 4
Figure 4
The potential roles of CD4+ cells in prion disease. Notes: CD4+ cells can be skewed into a TH2 or Treg phenotype in prion disease. TH2 cells may aid in the differentiation of antibody-producing plasma cells from B-cells. TH2 cells could increase the number and efficiency of secreted therapeutic antibodies by inducing an Ig class switch that could aid treatment of prion or neurological diseases. They may also be beneficial in advanced or familial prion disease by secreting proinflammatory cytokines that may attract macrophages to the brain in an attempt to clear prion deposits. Treg cells can secrete the cytokines IL-10 or TGFβ to decrease inflammation when necessary. Abbreviations: Ig, immunoglobulin; IgA, immunoglobulin A; IgG, immunoglobulin G; IL-4, interleukin 4; IL-10, interleukin 10; IL-13, interleukin 13; Treg, T regulatory cells; TH2, T helper 2; TGFβ, transforming growth factor beta.

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