Indirect T Cell Allorecognition of the RT1.Aa MHC Class I Molecule

Lovegrove, Emma (1999) Indirect T Cell Allorecognition of the RT1.Aa MHC Class I Molecule. PhD thesis, University of Glasgow.

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The extent to which the indirect pathway of T cell recognition contributes to graft rejection remains to be clarified, and this thesis examines its role in the antibody-mediated rejection of allografts in the MI-IC class I disparate rat strain combination, PVG-R8 (RT 1. AaB/CuDu) to PVG-RT 1" (RT 1. AuB/CuDu). A series of overlapping 15-mer allopeptides (Pl-P18) derived from the donor Aa antigen, were used to map the immunogenic, dominant and sub-dominant epitopes of the Aa molecule. Analysis of the alloantibody response mounted to individual allopeptides following their subcutaneous administration suggested that the 15-mer peptides P7 and P16, derived from the hypervariable regions of the alpha1 and alpha2 domains respectively, and the 24 amino acid al peptide were immunogenic. The dominant T cell epitope was characterised by examination of the in vitro T cell proliferative responses to individual allopeptides by LNC from RT1u animals immunised with Aa-bearing R8 allografts. Proliferation focused upon those peptides derived from the hypervariable region of the al domain, an area corresponding to P7 and P8. Analysis of the alloantibody response to the intact Aa molecule following peptide priming demonstrated the presence of two additional sub-dominant T cell epitopes located within P1 and P9. These peptides derive from areas of the Aa molecule that are identical in amino acid sequence to the corresponding areas of the RT1u molecule, and are therefore, in effect, self-RT1u peptides. Priming with both dominant and sub-dominant epitopes accelerated the rejection of subsequent R8 cardiac allografts, suggesting that peptide priming is able to indirectly activate recipient T cells. It was examined whether the dominant and sub-dominant T cell epitopes could be used to favourably modulate the immune response to the intact Aa molecule by intravenous administration of high doses of P7 and P1 to RT1u animals before challenge with an R8 blood transfusion. Downregulation of the cytotoxic and IgM alloantibody responses were observed and in addition, P7 was able to downregulate the IgG2b response. Slight downregulation of the cytotoxic alloantibody response to an R8 cardiac allograft was seen following immunisation with P7, but the IgM and IgG2b responses were unaltered. Prolonged allograft survival was not observed. These results suggest that the indirect response to an allogeneic MHC molecule may involve additional unexpected epitopes and consequently, that the success of peptide-based tolerogenic protocols requires a fuller understanding of this process.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Eleanor Bolton
Keywords: Medicine, Immunology
Date of Award: 1999
Depositing User: Enlighten Team
Unique ID: glathesis:1999-76146
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Dec 2019 09:15
Last Modified: 19 Dec 2019 09:15

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