Monoclonal Antibodies in Solid Organ Transplantation

INTRODUCTION

Administration of targeted immunosuppression, in the form of genetically engineered antibodies, is commonplace in solid organ transplantation. Polyclonal antibodies, such as rabbit anti-thymocyte globulin, offer global immunosuppression by target-ing several cell surface antigens on B- and T-lymphocytes. However, secondary to their broad therapeutic targets, they are associated with infection, infusion related reactions, inter-batch variability, and post-transplant malignancy. Nevertheless, polyclonal antibodies are still commonly administered for in-duction and treatment of allograft rejection and offer an important role in current solid organ transplanta-tion, which is beyond the scope of this chapter.

In an attempt to target solid organ transplant immunosuppression, monoclonal antibodies directed against key steps in specific immunologic pathways were introduced. The first agent, muromonab-CD3, was initially introduced in the early 1980s for the treatment of allograft rejection (Morris, 2004). The use of monoclonal antibodies has evolved and expanded over the past two decades and today are routinely included as part of the overall immunosuppression regimen. Both the innate and adaptive immune systems have multiple components and signal trans-duction pathways aimed at protecting the host from a foreign body, such as transplanted tissue. The ultimate goal of post-transplant immunosuppression is tolerance, a state in which the host immune system recognizes the foreign tissue but does not react to it. This goal has yet to be achieved under modern immunosuppression secondary to immune system redundancy as well as the toxicity of currently available agents. Therefore, monoclonal antibodies are used to provide targeted, immediate immunomo-dulation aimed at attenuating the overall immune response. Specifically, monoclonal antibodies have been used to (1) decrease the inherent immunoreac-tivity of the potential transplant recipient prior to engraftment, (2) induce global immunosuppression at the time of transplantation allowing for modified introduction of other immunosuppressive agents (calcineurin inhibitors or corticosteroids), (3) spare exposure to maintenance immunosuppressive agents, and (4) treat acute allograft rejection. Monoclonal antibody selection, as well as dose, is based on patient specific factors; such as, indication for transplantation, type of organ being transplanted, and the long-term immunosuppression objective. To understand the approach that the transplant clinician uses to deter-mine which agent to administer and when, it is necessary to briefly describe how immunoreactivity can be predicted and review the immunological basis for the use and development of monoclonal anti-bodies in solid organ transplantation.