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Title: Immunomodulation in the NOD mouse
Author: Barber, K. A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1999
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A CD8+ T cell clone was generated by priming non-diabetic NOD mice with C2, a Kd-binding, 10-mer peptide (WYIPQSLRGV) derived from the large isoform of GAD. This clone (αC2.4) lyses NOD fibroblast targets transfected with a construct encoding human GAD67. This molecule is entirely homologous with mouse and rate GAD67 at the C2 region and as such this observation indicates that C2 is a naturally processed epitope. The object of this project was to investigate the role of the C2 epitope and altered peptide ligand (APL) derivatives in IDDM pathogenesis in the NOD mouse, with the ultimate aim of modifying disease by induction of antigen specific tolerance. Adoptive transfers into neonatal NOD and NOD-scid recipients have shown αC2.4 not to cause disease. Neither do these cells home to the pancreas. Surface marker characterization demonstrated that αC2.4 did not express β7 integrin, a horning receptor thought to play a key role in infiltration of the pancreas by autoreactive cells. However, administration of the C2 peptide was shown to reduce the incidence of spontaneous but not cyclophospamide induced disease, although this effect was dependent on the route of administration. Knowledge of the specificity of the CD8+T cell clone allowed investigation of the nature of T cell recognition of peptide/MHC as a basis for the search for an APL. Three residues of positions 5, 7 and 8 of the C2 peptide were shown to be critical for recognition of peptide/MHC by αC2.4. On the basis of these findings variant peptides were synthesized and screened by antagonistic properties. None was identified with the ability to alter recognition of C2/MHC by αC2.4. Cytokine intervention has been shown to be an important approach for immune modulation in IDDM in the NOD mouse. The aim of this aspect of the project was to use recombinant retroviral vector technology to modify islet specific T cell clones for targeted expression of immunosuppressive cytokines. Transduction of T cells was achieved although the efficiency of this process was limited. This approach may prove useful in altering the local cytokine milieu towards a non-pathogenic Th2 environment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available