title: 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.
authors: UPMC Univ Paris 6, UMR_S 938, Centre de Recherche Hôpital Saint-Antoine, Paris, France.
authors: Saci
authors: S
authors: Iken
authors: Véronique
authors: V
authors: Bachy
authors: Pauline
authors: P
authors: Gourdain
authors: Annick
authors: A
authors: Lim
authors: Sylvie
authors: S
authors: Grégoire
authors: Thomas
authors: T
authors: Chaigneau
authors: Pierre
authors: P
authors: Aucouturier
authors: Claude
authors: C
authors: Carnaud
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D022801:Complementarity Determining Regions; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D015847:Interleukin-4; D051379:Mice; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000276:immunology; D011328:Prions / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D012608:Scrapie / Q000517:prevention & control*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D022801:Complementarity Determining Regions; D018620:PrPSc Proteins; D011328:Prions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015847:Interleukin-4