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  • Review Article
  • Published:

Antiprion immunotherapy: to suppress or to stimulate?

Nature Reviews Immunology volume 4, pages 725–736 (2004)Cite this article

Key Points

  • 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.

Abstract

Although human prion diseases are rare, they are invariably fatal, and treatments remain elusive. Hundreds of iatrogenic prion transmissions have occurred in the past two decades, and the bovine spongiform encephalopathy epidemic has raised concerns about prion transmission from cattle to humans. Research into therapeutics for prion disease is being pursued in several centres and prominently includes immunological strategies. Currently, the options that are being explored aim either to mobilize the innate and adaptive immune systems towards prion destruction or to suppress or dedifferentiate the lymphoreticular compartments that replicate prions. This article reviews the pathophysiology of prion diseases in mouse models and discusses their relevance to immunotherapeutic and immunoprophylactic antiprion strategies.

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Figure 1: The prion hypothesis.
Figure 2: Dissemination of prions in scrapie-infected sheep or goats.
Figure 3: Models of the signalling pathways required for the establishment and maintenance of functional follicular dendritic cells.
Figure 4: Immunotherapeutic strategies for prion disease.
Figure 5: PrPSc accumulates in the germinal centres of lymphoid follicles in prion-infected lymph nodes.
Figure 6: Treatment with CpG ODNs leads to lymphoid germinal-centre destruction.

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Acknowledgements

We thank Markus Glatzel for critical comments. This work is supported by the University of Zürich (Switzerland), and by grants from the Bundesamt für Bildung und Wissenschaft (Switzerland), the Swiss National Foundation, the National Center for Competence in Research on neural plasticity and repair (Switzerland), the United States Department of Defense (National Prion Research Program), the Stammbach Foundation (Switzerland), Nestlé S.A. (Switzerland) and the National Institutes of Health (United States).

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  1. Institute of Neuropathology, University Hospital Zürich, Schmelzbergstrasse 12, Zürich, CH8091, Switzerland

    Adriano Aguzzi & Christina J. Sigurdson

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  1. Adriano Aguzzi
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Correspondence to Adriano Aguzzi or Christina J. Sigurdson.

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DATABASES

Entrez Gene

CXCR5

IFN-α receptor

IFN-γ receptor

LT-α

LT-βR

MyD88

PrPC

RAG1

TLR9

TNF

TNF receptor

ZAP70

Infectious Disease Information

BSE

CJD

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Adriano Aguzzi's homepage

National CJD Surveillance Unit

Glossary

ENCEPHALOPATHIES

A general term for diseases that affect the brain, including metabolic, toxic, traumatic, infectious and neoplastic disorders. Although it is used to describe the lesions that are caused by prion diseases, transmissible spongiform encephalopathies also affect the spinal cord.

SUPEROXIDE DISMUTASE

An antioxidant enzyme that contains zinc, manganese or copper, and protects cells from damage by superoxide radicals.

PRION HYPOTHESIS

Maintains that transmissible spongiform encephalopathies are infectious diseases caused by the conversion of a host-encoded, protease-sensitive protein — known as the prion protein (PrP) — to an abnormal, protease-resistant isoform. The hypothesis also states that the infectious agent is completely devoid of nucleic acids. The abnormal or disease-associated PrP (known as PrPSc) self-aggregates and forms amyloid fibrils. PrPSc has been identified as the main component of the infectivity.

TEMPLATE-DIRECTED REFOLDING

A model for prion conversion in which a single molecule of exogenously introduced abnormal (disease-associated) prion protein (PrPSc) interacts with and converts endogenous cellular prion protein (PrPC) to a PrPSc conformation. Spontaneous conversion is potentially prevented by a high-energy barrier, the crossing of which is required for conversion to amyloidogenic PrPSc.

SEEDING

A prion-conversion model (also known as nucleation), in which cellular prion protein (PrPC) and abnormal (disease-associated) prion protein (PrPSc) are in a thermodynamic equilibrium that favours the PrPC conformation. A highly ordered 'seed' of PrPSc might form, by which monomeric PrPSc can be recruited and stabilized, eventually forming an amyloid fibril. Fragmentation of the PrPSc aggregates increases the number of seeds and the potential for recruiting additional monomeric PrPSc molecules.

TOLL-LIKE RECEPTORS

(TLRs). A rapidly growing family of receptors that recognize pathogen-associated molecular patterns, which are conserved molecular patterns that are common to large groups of microorganisms and/or viruses. For example, TLR4 recognizes bacterial lipopolysaccharide, and TLR5 recognizes bacterial flagellin. Activation signals from TLRs are relayed through cytoplasmic adaptor proteins, leading to the transcription of genes that encode cytokines.

FOLLICULAR DENDRITIC CELLS

(FDCs). Cells with a dendritic morphology that are present in the lymphoid germinal centres, where they present intact antigens (which are either held in immune complexes or associated with complement receptors) to B cells. FDCs are of non-haematopoietic origin and are not related to dendritic cells.

SYMPATHETIC NERVE

A nerve that is part of the functional division of the autonomic nervous system that innervates the heart, lungs, gastrointestinal tract and sweat glands.

PATHOGEN-ASSOCIATED MOLECULAR PATTERN

A molecular pattern that is found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors.

UNMETHYLATED CpG MOTIFS

DNA containing an unmethylated cytosine– guanosine sequence. Such sequences are prevalent in bacterial DNA but rare in mammalian DNA. Unmethylated CpG is endocytosed by cells of the innate immune system and interacts with Toll-like receptor 9, activating a signalling cascade that results in the production of pro-inflammatory cytokines.

CYTOKINE STORM

A sudden surge in the circulating levels of pro-inflammatory cytokines, such as interleukin-1, interleukin-6, tumour-necrosis factor and interferon-γ.

BLOOD–BRAIN BARRIER

A barrier that is formed by tight junctions between endothelial cells and markedly limits the entry to the central nervous system of leukocytes and all large molecules, including (to some extent) immunoglobulins, cytokines and complement proteins.

LIPID RAFTS

Specialized membrane domains that are enriched in cholesterol, glycosphingolipids and proteins that function in signal transduction. Rafts are often equated with 'detergent-resistant membranes', which can be isolated by density-gradient centrifugation as a function of their high buoyancy.

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Aguzzi, A., Sigurdson, C. Antiprion immunotherapy: to suppress or to stimulate?. Nat Rev Immunol 4, 725–736 (2004). https://doi.org/10.1038/nri1437

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