Adoptive Transfer of T Lymphocytes Sensitized against the Prion Protein Attenuates Prion Invasion in Scrapie-Infected Mice

Abstract

There is to date no effective way of preventing or curing neurodegenerative diseases such as Alzheimer disease or transmissible spongiform encephalopathies. The idea of treating those conditions by immunological approaches has progressively emerged over the last ten years. Encouraging results have been reported in Alzheimer disease and in peripheral forms of mouse prion diseases following passive injection of Abs or active immunization against the peptides or proteins presumably at the origin of those disorders. Still, major difficulties persist due to some characteristics of those conditions such as slow evolution, brain location, uncertainties regarding precise pathogenic pathways, and, above all, the fact that the target Ag is self, meaning that it is poorly immunogenic and potentially harmful if tolerance was transgressed. To analyze some of those difficulties, we are developing adoptive cell transfer approaches. In this study, lymphocytes sensitized against the prion protein in nontolerant Prnp−/− mice were transferred into histocompatible wild-type recipients which were partly or totally devoid of their own lymphocytes. Under such conditions, we found that the engrafted T lymphocytes resisted peripheral tolerance, remained reactive for several months against epitopes of the prion protein, and significantly attenuated the progression of prions in secondary lymphoid organs with subsequent delay in the evolution of the neurological disease. Interestingly, those protective T lymphocytes secreted lymphokines and migrated more readily into the host CNS but did not appear to be engaged in cooperation with host B cells for Ab production.

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

“…Contrasting with the highly rigid selection at work in the thymus, the periphery appears to be more permissive, notably to primed T cells. As previously suggested [13], naive anti-PrP precursors may be more receptive to peripheral regulation. It is worth noting that, far from being inhibited, specific T cells proliferated more vigorously in scrapie-infected mice.…”

“…Having previously shown that PrP-sensitized polyclonal T cells attenuate scrapie evolution [13], we undertook to confirm those conclusions with transgene-bearing CD4 + T cells. Two ×10 5 CD4 + BV12 + primed T cells were transferred after sorting into CD3ε o/o mice which had been infected 1 day before with 2×10 4 LD 50 of the prion strain 139A.…”

“…Two strategies borrowed from cancer immunotherapy have already been probed for that purpose: dendritic cell (DC) vaccination [12] and adoptive CD4 + T cell therapy [13]. Improving T-cell-based immunotherapy, however, requires deeper insights into several issues.…”

Prion Protein Is a Key Determinant of Alcohol Sensitivity through the Modulation of N-Methyl-D-Aspartate Receptor (NMDAR) Activity

“…Because PrP −/− mice are on a C57BL6/Jx129/Sv mixed genetic background, we used the hybrid strain of C57Bl6/J x 129/Sv as wt controls. To control for the possible influence of the genetic background, homozygous knockout and over-expressing mouse PrP gene mice onto pure C57BL6/J background were also used [21], [22]. To do so, heterozygote mating pairs, inbred for at least ten generations onto C57BL6/J background, were mated to produce homozygous (noted as PrP −/− B6 and tga 20 B6 ) and wt (wt B6 ) littermates.…”

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

“…CD4 + T cell response against two PrP peptides in complete Freund's adjuvant led to a reduction in PrP Sc level in prion-infected N2a tumor grafts (Souan et al, 2001). 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).…”