Abstract and Introduction
Abstract
There has been increasing interest in the role played by B cells, plasma cells and their associated antibody in the immune response to an allograft, driven by the need to undertake antibody-incompatible transplantation and evidence suggesting that B cells play a role in acute cellular rejection and in acute and chronic antibody-mediated rejection. A number of immunosuppressive agents have emerged which target B cells, plasma cells and/or antibody, for example, the B cell-depleting CD20 antibody rituximab. This review describes recent developments in the use of such agents, our understanding of the role of B cells in alloimmunity and the application of this knowledge toward novel therapies in transplantation. It also considers the evidence to date suggesting that B cells may act as regulators of an alloimmune response. Thus, future attempts to target B cells will need to address the problem of how to inhibit effector B cells, while enhancing those with regulatory capacity.
Introduction
Over the past two decades, immunosuppressive strategies in solid organ transplantation have focused on depleting T cells or inhibiting their function. However, there has been increasing interest in the role played by B cells, plasma cells and their associated antibody, in the immune response to an allograft, initially driven by the need to reexplore the feasibility of antibody-incompatible transplantation. ABO-incompatible living donor renal transplantation is now widely offered, leading to the notion that the deleterious effects of B cells and antibody on allograft survival can be overcome. However, human leucocyte antigen (HLA)-incompatible transplantation remains a challenge, particularly in recipients of deceased donor organs, where a timely desensitization programme may not be feasible. This is a pressing issue for heart and lung transplant recipients, many of whom are sensitized prior to transplantation. The appearance of de novo donor-specific antibodies (DSA) and the development of acute antibody-mediated rejection (AMR) can also negatively impact on allograft survival, particularly if this occurs after the early post-transplant period. In addition, there is an increasing appreciation that B cells may play a role in acute cellular rejection (ACR) and perhaps more significantly, in chronic allograft attrition, in the guise of chronic AMR. In response to these clinical needs, a number of immunosuppressive agents have emerged which target B cells, plasma cells or antibody. Many of these agents were initially used in hemo-oncology for the treatment of B cell or plasma-cell malignancies, and were subsequently adopted for the treatment of B-cell-mediated autoimmune diseases and in transplantation. In this review, I will outline recent developments in our understanding of the processes involved in B-cell activation and the generation of alloantibody and how this can be applied to identify new therapeutic targets in transplantation. I will also consider the growing body of evidence demonstrating that B cells can not only act as effectors, but may also negatively regulate or modulate immune responses. Thus, the therapeutic goal is no longer simply one of B-cell depletion, as this may have deleterious effects on long-term transplant outcomes, but may require more subtle approaches to manipulate different B-cell subsets.