Induction of Immunological Tolerence to Kidney Allografts Following Donor-Specific Blood Transfusion: Experimental Studies in the Rat

Tweedle, James R (1997) Induction of Immunological Tolerence to Kidney Allografts Following Donor-Specific Blood Transfusion: Experimental Studies in the Rat. MD thesis, University of Glasgow.

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Donor-specific blood transfusion (DSBT) prior to renal transplantation has been known to have a beneficial effect on graft survival for over twenty years. In experimental models the magnitude of this effect is markedly strain-dependent. Two principal MHC disparate rat strain combinations were used to examine possible mechanisms of DSBT induced tolerance of renal allografts in this study. The first of these was an established model where a single pretransplant blood transfusion produces tolerance (DA into PVG: fully MHC disparate). The second (R8 into RT1u: class I-disparate) involved the development of a new model where DSBT alone was ineffective but the addition of a short course of cyclosporin A (15mg/kg/day for 7 days) at the time of the first of 4 weekly blood transfusions induced tolerance. In the first model, DA into PVG, over 80% of animals showed long-term acceptance of a kidney allograft following a single I ml DSBT 7 days prior to transplant. The tolerance was not tissue-specific and was independent of the thymus gland. Graft adaptation was seen in this model as passenger leukocyte depleted grafts survived for approximately 100 days in unmodified hosts (normal rejection time < 10 days). Cytokine levels present in rejecting, enhanced and syngeneic grafts were examined by semi-quantitative PCR. Levels of IFN-gamma, IL-4 and IL-10 were broadly similar in rejecting and enhanced grafts but the peak in IL-2 message around 4 days following transplant in the rejecting grafts was abrogated in the enhanced grafts. In the second model, R8 into RT1U, tolerance was again achieved in >80% of animals and was independent of the thymus gland. No evidence was seen for graft adaptation. Graft acceptance following DSBT/cyclosporin A-pretreatment correlated with low levels of cytotoxic alloantibody while DSBT alone led to high alloantibody levels and graft rejection. Interestingly the production of intragraft Th2 cytokines correlated with graft rejection rather than tolerance. This observation may reflect the immunological role of alloantibody in causing graft damage in this experimental model whereas in other models alloantibody may tend to favour tolerance rather than rejection. This protocol for tolerance induction was also shown to be effective in a fully disparate strain combination (DA into Lewis) where it was found that increasing the number of transfusions improved graft survival. Both of these models suggest that DSBT-pretreatments have a potential role in clinical practice especially when cyclosporin A is likely to be used as the principle immunosuppressant. DSBT is currently used in a small number of transplant centres but a greater understanding of the underlying mechanisms and development of a more effective protocol is required if its use is to become widespread.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: J A Bradley
Keywords: Medicine, Immunology
Date of Award: 1997
Depositing User: Enlighten Team
Unique ID: glathesis:1997-75924
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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