Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.640366
Title: Donor specific hyporesponsiveness in renal transplant recipients
Author: Alfonzo, Annette
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Abstract:
A phenomenon called donor-specific hyporesponsiveness (DSH) has been described in some renal allograft recipients, in which there is progressive loss of responsiveness to donor tissues and this has been shown to be associated with a favourable long-term outcome. Despite its potential clinical importance, the mechanisms of DSH are unknown and there are no laboratory tests that accurately predict its development in individual patients which might allow the reduction of immunosuppressive therapy. Here I test the hypothesis that renal allograft recipients with DSH can be identified by analysis of the mixed lymphocyte reactivity in-vitro and that this state will be accompanied by the production of inhibitory cytokines such as IL-10 and TGF-β. The study comprised 78 patients from a single centre, 60 of whom were studied retrospectively and 18 prospectively over a one-year period. DSH was detected by donor specific mixed lymphocyte reactions and cytokine production was analysed by ELISA and PCR. Overall, DSH was found in 61% of cadaveric and 57% of livingrelated recipients in the retrospective cohort and in 36% of cadaveric and 25% of living-related recipients at one year post-transplant in the prospective cohort. DSH was associated with a lower incidence of late acute rejection in cadaveric and livingrelated recipients in both arms of the study. Chronic rejection was found in some patients, even in the presence of DSH, indicating that DSH is not exclusive to patients with a good allograft outcome. DSH correlated with a good graft outcome in long-term cadaveric recipients and was associated with low donor-specific IL-2 and high IL-4 production. Similarly, good graft outcome and DSH was associated with a trend towards low donor-specific IL-2 and high IL-4 production within the first year post-transplant. However, in long-term living-related recipients, DSH did not correlate with graft outcome and was associated only with low IL-2 production. A sub-group of cadaveric recipients with a de-novo solid organ malignancy shared many similar clinical and immunological features with their counterparts who did not have malignancy. This included good graft outcome, low acute rejection rate and a high incidence of DSH. Patients with malignancy produced low levels of IL-2, but also produced high levels of IL-10. However, there was no evidence of immune regulation mediated by IL-10 or TGF-β in any part of the study. My results suggest that it may be possible to select patients for tailoring of immunosuppression on the basis of detection of DSH, together with the production of a favourable cytokine profile at one year post-transplant. Potential candidates include cadaveric recipients with stable graft function who show DSH and produce four-fold higher levels of donor-specific IL-4 than IL-2, as well as HLA-ID living-related recipients with stable graft function who produce low levels of donor-specific IL-2.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.640366  DOI: Not available
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