Abstract
Immune mediated injury is a major cause of late kidney graft loss. Donor specific HLA antibodies are widely believed to cause chronic rejection because their presence correlates strongly with worse graft outcome. However, some renal transplant recipients have circulating DSA for many years whilst maintaining stable graft function. This dichotomy has led to the hypothesis that the cause of the immune mediated damage observed in chronic rejection is likely to be multi-factorial.It has previously been demonstrated that donor specific CD4+ T cell activation can be observed in patients with chronic antibody mediated rejection using an IFNγ ELISpot assay. In some samples, this cellular activation was dependent on the presence of B cells, and in others the cellular activation appeared to be regulated by the presence of B cells.
In this thesis, the same patterns of reactivity were observed in renal transplant recipients with chronic antibody mediated rejection recruited onto the RituxiCAN C4 clinical trial. HLA binding B cells were detected flow cytometrically and associations between their phenotype and the different patterns of reactivity were analysed. The majority of HLA binding B cells were found to be IgM+ and were underrepresented in the class switched memory B cell population (CD27+IgM-/CD45RBmem55+IgM-) relative to the global B cell population. B cell dependent IFNγ production in response to donor specific HLA was associated with a higher ratio of IgM+ memory to IgM+ naïve B cells in the HLA binding B cell population.
CMV gB was used as a model protein to investigate the individual contribution that memory (CD27+) and naïve (CD27-) B cells make to antigen specific IFNγ production. The results suggest that memory B cells support IFNγ production and naïve B cells may be suppressing IFNγ production.
Collectively the results in this thesis support a role for a cell-mediated component in chronic antibody mediated rejection. In order to develop more effective treatments for chronic rejection, further investigation into the contribution that T and B cells make to this process is warranted.
| Date of Award | 2016 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Anthony Dorling (Supervisor) & Giovanna Lombardi (Supervisor) |