Antiprion immunotherapy: to suppress or to stimulate?

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Abstract
Prion diseases are progressive, ultimately fatal neurological disorders. They are unique in that they are transmissible. The latency period in prion diseases is extremely long, which provides a window of time to exploit potential interventional strategies before clinical symptoms arise. Examples of prion diseases are bovine spongiform encephalopathy in cows, scrapie in sheep, chronic wasting disease in deer and elk, and Creutzfeldt–Jakob disease in humans. Scrapie has been known to exist for more than two centuries. No experiments have so far unambiguously shown that the disease-associated prion protein (PrPSc) is the transmissible agent, but it is known to be an important component of prion infectivity. The function of the cellular prion protein (PrPC) is not clear. Neuronal cytotoxicity of PrPSc depends on the expression of PrPC. Evidence indicates that the conversion of PrPC to PrPSc is deleterious, but the mechanism of neural degeneration is still unclear. Several prion diseases are transmitted by ingestion of prion-contaminated food. After prion uptake, a replication phase occurs in lymphoid tissue before invasion of the nervous system. The abnormally folded, aggregated PrPSc is amplified in the lymphoid germinal centres, probably by follicular dendritic cells and tingible-body macrophages, and possibly by other lymphoid cells. Depletion of mature follicular dendritic cells delays the development of prion disease after intraperitoneal inoculation, so this might be considered as a post-exposure prophylactic strategy. Vaccination has so far been unsuccessful in the generation of effective PrP-specific antibody responses in mice because of tolerance to PrPC. Furthermore, therapy with CpG-containing oligodeoxynucleotides, using a multi-dose regimen, causes unwanted toxic side-effects. However, another option for treatment might be administration of a dimeric PrP molecule fused to the Fc portion of IgG1, as this has been shown to antagonize prion accumulation. Other chemical modifiers that disrupt prion accumulation in vitro include Congo red, amphotericin B, anthracycline derivatives, sulphated polyanions, pentosan polysulphate, soluble lymphotoxin-β receptors, porphyrins, branched polyamines and β-sheet-breaker peptides.