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Title: Immunogenicity and immune function of the cellular prion protein
Author: Isaacs, J. D.
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Prion protein (PrP) is the only factor known to be essential in the pathogenesis of the transmissible spongiform encephalopathies (TSEs) or prion diseases. The cellular isoform (PrPc), a GPI-anchored sialoglycoprotein of unknown function, has an identical primary structure to the disease-associated conformer (PrPSc). Thus, animals are tolerant to PrPSc and TSEs do not trigger a classical immune response. Vaccine development for human TSEs requires elucidation of the immunodominant human T cell epitopes within PrP. Further, successful immunotherapy requires that the function of PrPc in lymphocytes is understood, as therapeutic targeting of prion protein risks interfering with immune function. Peripheral blood leukocytes from healthy donors were cultured with PrP sequence peptides to elicit proliferative and cytokine responses. Responses were seen to peptides clustered around the position 129 polymorphism and the C-terminus, in accordance with a predictive algorithm. The substitution of methionine by valine at position 129 altered both epitope immunogenicity and cytokine profile. Studies in murine T cell activation models demonstrated transcriptional and late surface protein upregulation of PrPc. Memory T cells expressed higher PrPc levels than naive cells and there was also a strong correlation at both protein and transcriptional levels between expression of PrPc and the regulatory T cell marker, Foxp3. Embryonic deletion of Prnp did not lead to deficits in T cell conjugation, proliferation or cytokine production, although memory cell numbers were slightly reduced. In PrP*7" mice regulatory T cells developed normally but may have enhanced suppressor function. However, neither PrP ablation nor anti-PrP monoclonal antibodies altered the phenotype of T cell mediated autoimmune disease. These findings demonstrate that tolerance to PrP is not complete in humans and raise the prospect of generating protective immunity through vaccination. However, PrPc is a potentially important memory, regulatory and T cell activation antigen, therapeutic disruption of which may precipitate immunopathology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available