Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
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1136 ADRIANO AGUZZI AND ANNA MARIA CALELLA<br />
FIG. 10. Immunotherapeutic strategies for prion disease. A: treatment with the lymphotoxin- receptor fusion protein (LTR)-Ig breaks up the FDC<br />
networks <strong>and</strong> disrupts lymphoid follicles. The best protection is achieved when the fusion protein is administered immediately after exposure to prions.<br />
B: ablation of mature follicular dendritic cells (FDCs) delays the development of prion disease in mice. However, treatment with multiple doses of<br />
CpG-containing oligodeoxynucleotides (CpG ODNs) produces severe unwanted side effects, including immunosuppression, liver necrosis, <strong>and</strong> thrombocytopenia.<br />
C: vaccination against a self-protein is difficult because of immune tolerance, <strong>and</strong> it has the potential to induce autoimmune disease. Transgenic<br />
expression of an immunoglobulin chain containing the epitope-interacting region of 6H4, a high-affinity anti-PrP monoclonal antibody, associated with<br />
endogenous <strong>and</strong> chains, leads to high anti-PrP C titers in Prnp o/o <strong>and</strong> Prnp / mice. It suffices to block prion pathogenesis upon intraperitoneal prion<br />
inoculation. After active immunization with full-length PrP in attenuated Salmonella vector, the mice develop high PrP specific antibody titers. D: treatment<br />
with dimeric full-length PrP fused to the Fc portion of human IgG1 (PrP-Fc 2) delays the development of prion disease in mice, most probably owing to<br />
its interaction with the disease-associated PrP (PrP Sc ). LT- 1 2, LT heterotrimer; TLR, Toll-like receptor.<br />
ising results in mouse scrapie (450). The delay in the<br />
development of prion disease in this model could be due<br />
to the destruction of the primary site of peripheral prion<br />
amplification, the lymphoid follicles (209). Alternatively,<br />
the massive expansion of macrophage <strong>and</strong> dendritic cells<br />
that is evident following repetitive CpG-ODN treatment<br />
Physiol Rev VOL 89 OCTOBER 2009 www.prv.org<br />
might lead to enhanced PrP Sc degradation or prion sequestration.<br />
Macrophages might conceivably function as prion<br />
transporters when exposed to high prion titers; on the<br />
other h<strong>and</strong>, they might also inhibit prion infectivity when<br />
confronted with manageable prion titers (48). However,