Th2-polarised PrP-specific Transgenic T-cells Confer Partial Protection against Murine Scrapie

Abstract

Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the ß-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes.

Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy

“…In a similar fashion, adoptive transfer of copolymer-1 immune cells results in neuroprotection in a mouse model for Parkinson's disease [155]. In a more disease-specific manner, Iken et al demonstrated that adoptive transfer of prion specific, Th2 polarized T-cells inhibited prion replication, and prolonged survival in mice challenged with scrapie [156]. The effect of antigen selection on T-cell responses was demonstrated for α -syn, where immunization with nitrated α -syn polarized CD4+ T-cells to a Th1 phenotype.…”

B Cell-Specific S1PR1 Deficiency Blocks Prion Dissemination between Secondary Lymphoid Organs

“…Prion disease does not invoke a specific humoural response (57), and disease pathogenesis is unaffected in mice deficient in antibody Fc-γ receptors or circulating immuoglobulins (48). This suggests that cognate (antigen [prion]-specific) capture by B cells via their B cell receptors is highly unlikely.…”

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

“…Adoptive transfer of CD4 + T cells specific for PrP [156][157][158][159][160][161][162][163][164][165][166][167][168][169][170] peptide was able to attenuate prion disease in scrapie-infected mice (Gourdain et al, 2009). The efficiency of CD4 + T cells was recently confirmed by the partial protection against the disease obtained after the transfer of transgenic T cells bearing a T cell receptor specific for PrP in the complete absence of PrP-specific antibodies (Iken et al, 2011). In these murine models, CD4 + T cells seemed to contribute to prion-disease protection and not to cause harmful reactions in the CNS that expresses high levels of PrP c and accumulates PrP Sc when infected.…”