Sawyer, Greta Jane; (1996) Studies of vascularised allograft and xenograft rejection pathways. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The role of indirect T cell allorecognition in transplantation has been investigated. Peptides from the alpha helical regions of class I MHC have been used in a rat kidney graft model to study the effect of priming to indirect T cell allorecognition on the efficacy of cyclosporin A immunosuppresion. The work in this thesis demonstrates that priming with peptide to indirect T cell allorecognition does not influence graft function or survival under cyclosporin A therapy. However cyclosporin A could not suppress the early antibody response seen to the grafts in the primed rats. Multiple blood transfusions given prior to grafting can lead to a prolongation of graft survival. To try to elucidate the mechanisms of this process LEW recipients were primed to indirect T cell allorecognition by immunisation with a DA class I peptide before or during multiple blood transfusions. These peptide immunisation studies suggest that multiple blood transfusion suppresses the T helper pathway The other main area of interest has been the study of the mechanisms of xenograft rejection, where indirect recognition could play a major role in the rejection process. In this thesis I have used various strategies to induce prolongation of survival of the concordant mouse-to-rat vascularised heterotopic heart graft model. Therapies including cyclosporin A, CTLA4-Ig and splenectomy were used. The rejection response between these closely related species was very vigorous. Marked prolongation of survival was seen when all three of the therapies were combined. Most of the recipients did not reject their grafts whilst under treatment. Interestingly nude rats also rejected their grafts in a similar time span to controls. Pathology of the grafts at the time of rejection indicated a mild infiltrate that was negative for T cell markers and contained polymorphonuclear cells. Rat antibodies to mice were detected at day 3 (the day of rejection), indicating a humoral rejection response. Recipients with grafts that survived past day 18 post transplant demonstrated a massive cellular infilitration of the graft at the time of rejection and no rat anti-mouse antibodies. These studies suggest that once the initial antibody-mediated phase has been overcome, cellular mechanisms might play a dominant role in the rejection response of these vascularised concordant cardiac xenografts.

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