Solid organ transplantation is now an established and effective treatment option for end-stage organ failure. Whilst early outcomes have improved significantly over recent decades, longer-term outcomes have changed little. Despite advances in immunosuppression, most transplanted organs suffer an inevitable decline in function attributed to chronic rejection. It is evident that the alloimmune response remains incompletely characterised. Crucially, despite description several decades ago, the precise contribution that the direct (recognition of intact allogeneic MHC) and indirect (recognition of self-MHC restricted allopeptide) pathways make to allograft rejection remains incompletely understood. In this thesis, murine models of heterotopic cardiac transplantation have been utilised to analyse these pathways. The key findings of this work are as follows: 1) If able to evade NK cell killing, passenger donor CD4 T cells can make cognate, direct-pathway, interactions with recipient B cells. This interaction results in augmentation of all arms of the alloimmune response and acceleration of allograft rejection. 2) Direct-pathway CD4 T cell allorecognition is restricted to the immediate post transplantation period. Donor APCs are the major source of MHC class II for direct-pathway priming, and these are cleared rapidly by both innate and adaptive responses of the recipient, effectively limiting the longevity of direct allorecognition. 3) The duration of indirect-pathway responses against different alloantigens is variable, limited by availability of donor antigen. Expression of donor MHC class II is restricted to APCs and possibly endothelium (where expression is transient) limiting the duration of indirect-pathway allorecognition against MHC class II alloantigen. Indirect-pathway CD4 T cell responses targeted against parenchymal alloantigen are long-lived, and can provide help for generating alloantibody against different MHC alloantigens. 4) In response to continual presentation of target epitope indirect-pathway CD4 T cell responses against parenchymal expressed alloantigen are long-lived. The continual division of these cells results in greatly increased numbers of alloantigen-specific CD4 T cells in the chronic phase of the response, but despite this, memory responses are impaired. 5) Generating indirect-pathway regulatory T cells specific for parenchymal expressed alloantigen appears to be the most effective strategy to ameliorating chronic rejection.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:675906 |
| Date | January 2015 |
| Creators | Ali, Jason |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/252879 |
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