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Title: Investigation of the mechanism of the beneficial effect of blood transfusion on rat renal allograft survival
Author: Armstrong, Hilary E.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1990
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Abstract:
In the rat renal allograft model, pre-operative administration of donor strain blood is sufficient to produce long-term renal allograft survival even in the absence of adjunctive immunosuppression. The precise mechanisms underlying this enhancing effect are unclear but possible mechanisms include elimination or clonal deletion of alloreactive lymphocytes, removal of passenger leucocytes, blocking of effector cells by antibody or antigen and the induction of alloantigen-specific suppressor cells. Rejecting rat renal allografts are characterised by a heterogeneous mononuclear cell and it was therefore important to determine whether pre-operative blood transfusion affected the infiltration of allografts. A detailed analysis was made of the pattern and phenotype of mononuclear cells infiltrating rejecting DA strain allografts in unmodified PVG recipients and non-rejecting DA allografts from PVG recipients which had been actively enhanced by injection of 1 ml of DA blood intravenously 7 days before transplantation. Excised grafts were stained with a range of monoclonal antibodies to rat cell surface antigens on day 1, 3, 5 and 7 post transplantation. Paradoxically pre-operative blood transfusion caused accelerated cellular infiltration of the graft and the rapid disappearance of graft interstitial dendritic cells. The phenotype of cells found within both enhanced and rejecting grafts was similar except for a reduced number of CD8+cells and IL-2 receptor positive cells in the enhanced compared with rejecting grafts at day 5 after transplantation. However,there was no concomitant decrease in levels of in vitro cytotoxicity, since graft infiltrating cells and splenocytes from transfused animals had comparable levels of both specific and non-specific cytotoxicity to those found in rejecting animals. Class I and class II MHC antigen expression within enhanced and rejecting grafts was studied since the distribution and density of MHC expression may influence the vulnerability of the graft to host effector responses. Unexpectedly it was found that enhanced grafts underwent an accelerated and extensive induction of both donor class I and class II MHC antigens. This suggested that pre-operative blood transfusion initially causes sensitisation of the recipient resulting in an accelerated immunological response to the allograft, but that this is rapidly and effectively suppressed by immunoregulatory mechanisms. The possibility that humoral factors may play a role in the beneficial effect of blood transfusion on graft survival was then investigated. Because of reports suggesting an association between serum Fc blocking activity and renal allograft survival, Fc blocking activity was measured in the serum of unmodified and transfused PVG recipients of a DA renal allograft. Serum harvested on day 5 from actively enhanced PVG recipients of a DA renal allograft was shown to specifically inhibit erythrocyte-anti body (EA) rosette formation with donor strain, but not third-party strain, splenocytes, while the levels of EA rosette inhibition in day 5 serum from rejecting rats was markedly lower. This FcR-blocking activity was present in enhanced serum fractions, prepared by discontinuous density gradient centrifugation, which corresponded to the 7S peak. Purified IgG prepared from enhanced serum was also found to inhibit EA rosette formation with donor splenocytes, and absorption of the IgG preparations with donor-strain erythrocytes failed to abrogate EA rosette inhibition. Further experiments, in which absorbed IgG from enhanced animals was tested for FcR-blocking activity against splenocytes of defined major histocompatibility complex (MHC) subregion specificities, established that FcR blocking activity was mediated by IgG alloantibodies directed against donor MHC class II antigens. This finding suggested that there might be important differences in the nature and timing of the alloantibody response to a renal allograft in rejecting and enhanced recipients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796441  DOI: Not available
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