Pathophysiological role of B cells and the therapeutic potential of anti-CD20 in chronic renal allograft rejection

50% of the patients who receive a kidney transplant (or ‘graft‘) will have to return dialysis within 10 years. One group at high risk are those who develop antibodies. To help prolong the grafts in these patients, this project aims to clarify precisely how antibodies are associated with graft damage. Approximately 60 patients with antibodies from within 300 transplant recipients will be identified. Further analysis will depend on whether their grafts are deteriorating. If so, blood and biopsy specimens will be examined to try and identify whether (and how) antibody is involved in the process of deterioration. All these patients will be offered treatment to stop their ‘B‘ lymphocytes (the cells that makes antibodies) from working, to see if this it affects the rate of graft deterioration. This therapy works well in other antibody-associated conditions and is generally safe to use. A small number of patients with antibodies are expected to have grafts that are working well. These patients will be studied to try and understand why antibodies or T cells do not damage their grafts. It is expected that this work will help understanding of the mechanisms of graft loss and should improve the prognosis of patients with failing transplants.

A significant cause of renal allograft failure is ‘chronic rejection‘ (CR), the pathophysiology of which is incompletely understood. Some patients (20-30%) develop anti-HLA antibodies before CR and it has been assumed that these antibodies cause the rejection. However, this assumption may not be correct. This project will clarify the relevance of anti-HLA antibodies after kidney transplantation, determine their relationship with CR, and undertake a pilot study of anti-CD20 therapy in these patients. Hypotheses: a) In CR, development of anti-HLA antibodies may indicate two types of damage, both linked by a role for B cells in pathophysiology; the antibody may be causing chronic humoral rejection or it may be a marker for a T cell-mediated process, with B cells playing a critical role in the presentation of graft antigens. b) However, anti-HLA antibodies may also be associated with transplant ‘accommodation‘ - this, rather than CR, is expected if patients develop low-titre anti-HLA antibodies and maintain effective mechanisms to regulate indirect T cell alloresponses. b) Targeting B cells using anti-CD20 therapy in patients with CR but not accommodation may help prevent graft loss. Aims and Methods: a) I will define, using FlowPRA , a subgroup of renal transplant patients who have anti-HLA atibodies and deteriorating graft function. Blood will be analysed to determine antibody specificity, and to assess whether B lymphocytes play a role as antigen presenting cells in indirect T cell alloresponses. A renal biopsy will be analysed for features of CR, C4d staining, B cell/plasma cell infiltration and T cell mediated rejection. b) A small number of patients with anti-HLA antibodies are expected to have stable graft function. Differences between these patients and those in group a) will be examined. In particular, the titres of antibodies and strength of indirect T cell responses will be analysed. A long-term follow-up study in these patients will be initiated. c) Patients with anti-HLA antibodies and deteriorating graft function will be offered anti-CD20 therapy. They will be followed up for 2 years, assessing for evidence of side-effects, changes in anti-HLA antibodies, stabilisation of transplant function and changes in strength of alloreactive T and B cell function. This study should lead to a greater understanding of the role of antibodies and B cells in CR and accommodation. This work is expected to eventually improve the prognosis of patients with failing grafts, thus having a significant impact on the lives of all renal transplant recipients.