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Title: Mechanisms of tolerance in a rat model of antibody-mediated allograft rejection
Author: Callaghan, C. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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This thesis tests the hypothesis that Tregs with indirect allospecificity can prevent humoral rejection. Anti-CD4 monoclonal antibody and PVG.R8 donor-specific blood transfusion (DST) given pre-transplant led to long-term PVG.R8 heart graft survival in two-thirds of PVG.RT1u recipients. Alloantibody production was abrogated in these animals and tolerance was allospecific. Histology of long-term surviving grafts showed no evidence of chronic rejection. Naïve syngeneic spenocytes injected into tolerant PVG.RT1u animals did not effect heart graft rejection, suggesting the presence of regulatory mechanisms. Adoptive transfer experiments into CD4+ T cell-reconstituted congenitally athymic PVG.RT1u rats confirmed that regulation in tolerant animals was mediated by spenic CD4+ T cells. These CD4+ Tregs were allospecific. Other mechanisms of tolerance in this model were explored by breaking regulation in tolerant rats, either by immunising with immunodominant linear allopeptide, or by depleting tolerant CD4+ T cells with anti-CD4 monoclonal antibody. Surprisingly, this resulted in neither alloantibody generation nor graft rejection, suggesting that tolerance also resides within alloantigen-specific B cells. These results demonstrated that anti-CD4 + DST treatments results in the development of CD4+ Tregs that recognise alloantigen via the indirect pathway and act in an antigen-specific manner to prevent alloantibody-mediated rejection. Their development is associated with intrinsic tolerance within the alloantigen-specific B cell component that persists after CD4+ T cell help has been made available. These findings may be of use in designing clinically-applicable tolerogenic strategies in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available