Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie

Abstract

Prion diseases are presumed to be caused by the accumulation in the brain of a pathological protein called prion protein (PrP) scrapie which results from the transconformation of cellular PrP, a ubiquitous glycoprotein expressed in all mammals. Since all isoforms of PrP are perceived as self by the host immune system, a major problem in designing efficient immunoprophylaxis or immunotherapy is to overcome tolerance. The present study was aimed at investigating whether bone-marrow-derived dendritic cells (DCs) loaded with peptides previously shown to be immunogenic in PrP-deficient mice, can overcome tolerance in PrP-proficient wild-type mice and protect them against scrapie. Results show that, in such mice, peptide-loaded DCs elicit both lymphokine release by T cells and antibody secretion against native cellular PrP. Repeated recalls with peptide-loaded DCs reduces the attack rate of 139A scrapie inoculated intraperitoneally and retards disease duration by 40 days. Most interestingly, survival time in individual mice appears to be correlated with the level of circulating antibody against native cellular PrP. INTRODUCTIONPrion diseases, also called transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders which progress slowly, induce severe neurological loss and are transmissible. The agent is most presumably the scrapie prion protein (PrP) or PrPSc, a misfolded protein, rich in beta-sheets, resulting from the transconformation of cellular PrP (PrPc). PrPc is a ubiquitous, membrane-anchored protein, which has been remarkably conserved through evolution, but whose function in health is still enigmatic. The presence of PrPSc in tissues of diseased individuals confirms the diagnosis TSE (Prusiner et al., 1998;Wisniewski et al., 1998).Prions do not spontaneously evoke antibody (Ab) or T-cell responses in diseased subjects, most likely because PrPSc, like PrPc, is not perceived as foreign or 'dangerous' (Matzinger, 1998) by the host immune system. In recent years, however, following encouraging immunotherapy results in Alzheimer's disease patients (Schenk et al., 1999), several teams have attempted to passively or actively generate adaptive immune responses against prions in wild-type (wt) mice and have shown that passive Ab treatment (Sigurdsson et al., 2003;White et al., 2003), constitutive transgenic secretion of anti-PrP IgM (Heppner et al., 2001) or active immunization using whole PrP (Sigurdsson et al., 2002), PrP peptides (Schwarz et al., 2003), PrP fragments (Bade et al., 2006) or DNA constructs encoding Prnp gene sequences (Fernandez-Borges et al., 2006) had beneficial effects on disease evolution.In order to identify major histocompatibility (MHC) class II-restricted T-cell epitopes in C57BL6 (B6)-H-2 b mice, we previously screened a bank of overlapping peptides of mouse PrP and identified two main epitopes. One is contained in peptide PrP , the other is shared by peptides PrP 143-172 and PrP . Immunization of mice made genetically deficient for PrP (Prnp 2/2 ) with PrP 97-1...

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

“…Many vaccination regimens in experimental mouse models of scrapie resulted in prolonged incubation periods, which were most often ascribed to anti-PrP antibodies (Pankiewicz et al, 2006;White et al, 2003;Peretz et al, 2001;Polymenidou et al, 2004;Bachy et al, 2010;Rosset et al, 2009). To our knowledge, our study constitutes the prime evidence that an immune manipulation can interfere with prion progression during the symptomatic period.…”

Evaluation of an α synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease

“…However, several studies have indicated that antigen sensitized DCs, when used as a vaccine, can overcome (i.e., break) immune tolerance. This has been specifically reported in a mouse model of scrapie induced by prion proteins, 47 as well as in mouse models of tumor induction 48 and hepatitis B infection. 49 Also, as previously indicated both a-Syn and Ab have successfully been able to stimulate antibody responses in appropriate Tg animal models.…”

The Immune System in the Pathogenesis and Prevention of Prion Diseases

“…More recently, research has focused on the initiation of T-cell based immunity in order to break the natural tolerance to PrP C . In one such study, dendritic cells were pre-loaded with prion protein peptides and injected into wild-type mice at 15 day intervals [111]. Spleen cells and sera collected 10 days after the final challenge demonstrated that T cells could be induced to produce a good lymphokine response as defined by Interferon-gamma and IL-4 release.…”