Benham, Adam Maurice; (1995) Indirect T cell allorecognition of donor MHC class I alloantigens. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The work in this thesis concerns the role of indirect T cell allorecognition as a component of allograft rejection, using the rat as a model. Previous studies in our laboratory have proven that indirect T cell allorecognition is an important effector mechanism in the rejection of MHC class I mismatched rat skin grafts. I have furthered this work to show that indirect recognition is also an important component of vascularised rat kidney allograft rejection. Interstitial dendritic cell free kidneys from (DAxLEW)F1 donor rats were transplanted into LEW RTI recipients that had been previously primed for indirect recognition with DA MHC class I-derived peptides. These animals showed accelerated graft rejection compared with unimmunised controls. A PVG RTIr1 into (PVGxLEW)F1 kidney transplantation model was also investigated, but was found to be unsuitable for unravelling the mechanisms of indirect recognition or for studying tolerance to our donor class I peptides. The fine specificity of peptide determinants involved in indirect T cell allorecognition in the rat was also investigated. A nested set of 15 amino acid peptides were synthesised; these were derived from a 24 amino acid peptide, P1 (from the DA RT1.Aav1 MHC class I molecule), known to accelerate rat skin graft rejection. The T and B cell responses to these derivative peptides were observed in the LEW, WAG and PVG rat strains: within the original 24mer, there is more than one T cell epitope towards which the LEW rat mounts a polyclonal T cell response. Furthermore, the number of T cell epitopes within P1 is strain specific. LEW rats with long surviving allografts, after a 10-14 day course of Cyclosporin A therapy, were assessed for the development of antibodies towards donor DA MHC class I molecules after grafting. Fifteen of 17 rats investigated have no donor MHC class I antibody response. The immune status of some of these rats was examined following P1 priming and was found to vary between individual animals.

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