- Dr Anthony Dorling, Principal Investigator
- Prof. Terence Cook, Co-Investigator
- Imperial College London, London, UK
- Understanding How Antibodies and B Cells Contribute to the ‘Chronic’ Rejection of Transplanted Kidneys
Chronic allograft nephropathy (CAN) resulting in loss of the transplant kidney is an important problem; – by 10–12 years after transplantation, approximately 50% of patients have returned to dialysis. A significant proportion of cases are due to ongoing immunologically mediated damage, or ‘chronic rejection’ (CR) and many of these have evidence of antibody-mediated pathology as evidenced by the deposition of complement component C4d in the peritubular capillaries or glomeruli of transplant biopsy specimens alongside the features of CAN. There is no established treatment for CR, although optimisation of immunosuppression to include tacrolimus and mycophenolate mofetil (MMF) achieves short-term stabilisation of function in approximately 4 out of 5 patients.
In late 2006, we are starting a randomised trial of anti-CD20 therapy in patients who fail to stabilise after initiation of an MMF/tacrolimus-based regime, with the goal of establishing the efficacy of anti-CD20 in this group. This application will fund scientific analyses of the patients entered into this trial, with the objective of analysing the contribution on non-HLA-specific antibodies and to determine whether B lymphocytes can be shown to be acting as antigen presenting cells (APC) for the allogeneic anti-graft T cell response. We hope to determine laboratory and biopsy criteria for predicting responsiveness to standard therapy or anti-CD20.
Additionally, we hypothesise that there are a subgroup of patients with CR without evidence of C4d deposition, in whom B cells may be playing an important role in pathology. We hypothesise that this subgroup develops circulating anti-HLA antibodies as a marker of this process. This application will fund laboratory studies in this group to define biopsy criteria for diagnosis, antibody specificities and to determine whether B lymphocytes are acting as APC for the allogeneic anti-graft T cell response, with the ultimate aim of establishing a rational basis for targeting therapy towards B cells in this subgroup.
Finally, it is now well established that anti-graft antibodies are not always associated with progressive graft deterioration, but can also be associated with ‘accommodation’, in which the transplanted kidney becomes resistant to the pathological effects of antibody. This application will fund a detailed study of our transplant recipients with stable function, to determine the nature and specificity of the antibodies in patients with accommodation and to examine the hypothesis that B cells in these patients also act as APC for allogeneic T cells, but in contrast to those with CR, these interactions take place in the context of effective peripheral immunoregulatory mechanisms, whereas in CR we hypothesise we will be able to demonstrate an absence of peripheral regulation.