Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 5, Issue 3, 2005

Although cell-mediated rejection has remained the most common form of graft rejection after organ transplantation, antibody-mediated rejection has recently gained much significance in clinical transplantation. New evidence points to an antibody-mediated rejection contributing not only to hyperacute and acute but also to chronic allograft rejection. In addition, in discordant xenotransplantation, severe forms of antibody-mediated rejection, including hyperacute rejection and acute humoral xenograft rejection, represent major immunological barriers to successful xenotransplantation. Antibody-mediated rejection in both allotransplantation and xenotransplantation typically does not respond to conventional anti-rejection therapy, so it has recently been recognized as a major cause of graft loss. Histopathology remains the most definitive and reliable tool for the diagnosis of graft rejection in both allografts and xenografts. In this review, we discuss the concept that microvascular injury is a characteristic feature of antibodymediated rejection that develops in hyperacute, acute and chronic antibody-mediated rejection in both allografts and discordant xenografts as well as in kidney and heart grafts. We also review work indicating that endothelial cell activation and endothelial cell death in the microvasculature can contribute to ultimate graft loss by triggering capillary destruction, interstitial hemorrhage, and platelet-rich microthrombi in hyperacute and acute antibody-mediated rejection as well as with the formation and progression of fibrotic scars in chronic antibody-mediated rejection.

Antibody-mediated barriers to renal transplantation, including donor specific anti-HLA and anti-blood group antibodies, have become an increasingly important issue over the last forty years as the organ shortage has continued to expand. The inevitable result of the unmet demand for compatible organs has been a continuous increase in recipient waiting times. Over the last decade, two treatment strategies have been developed to address this problem. These regimens rely on the immunomodulatory properties of intravenous immunoglobulin (IVIG) administered alone at relatively high doses, or at lower doses in combination with the non-selective depletion of antibodies from plasmapheresis. Both protocols have been successfully used for desensitization of patients with donor-specific anti-HLA antibody and have allowed for renal transplantation with excellent outcomes. The combined strategy of plasmapheresis/IVIG has also been successfully employed for renal transplantation in recipients of ABO blood group incompatible kidneys. This review will provide an overview of these therapies and their application to incompatible renal transplantation.

In order for ABO-incompatible organ transplantation to be performed successfully, the antibody response must be targeted. Aggressive strategies are usually required both to remove pre-existing antibodies directed at donor A/B antigens and to suppress further production of antibodies. If this can be accomplished in the short-term, graft accommodation of ABO-incompatible transplants may develop upon eventual re-accumulation of antibodies as the graft acquires resistance to antibody-mediated damage. In contrast to mature individuals, very young infants lack isohemagglutinins due to a natural lag in development of immunity to T cell-independent polysaccharide antigens. This delay in maturation permits a window of safety during which infants can receive ABO-incompatible grafts without the requirement for aggressive immunosuppressive strategies. We have recently demonstrated that ABO-incompatible heart transplantation performed during this stage of immaturity is followed by the spontaneous development of donor-specific B cell tolerance rather than graft accommodation, and that tolerance in this setting occurs by a cellular mechanism of antigen-specific B cell elimination. This finding is strikingly similar to the original descriptions of neonatal T cell tolerance in mice. Our data provide compelling justification that every effort should be made to include juvenile recipients routinely as subjects in tolerance research. Through understanding the mechanisms underlying tolerance in this setting, as with murine models of neonatal tolerance originally described by Medawar and colleagues, it may be possible to expand the potential applications of tolerance strategies to older patient populations.

Antibody-mediated mechanisms are central to the rejection that occurs when pig organs are transplanted into primates. In this article, the histopathological features of the humoral rejection process in these species combinations, namely hyperacute rejection and acute humoral xenograft rejection, will be illustrated. The profile of the natural and elicited antibodies involved will also be discussed. It has now been demonstrated that the natural immune response to a porcine xenograft is primarily directed to Galα1-3Gal (αGal) specificities, whilst the elicited immune response is directed to both αGal and non-αGal antigens. The principal characteristics of anti-αGal, anti-non-aGal and polyreactive antibodies will be described, together with the identification of the molecules recognised by natural and elicited xenoreactive antibodies. The role of the humoral immune response in the rejection of porcine islets in the primate is still uncertain and the current views on the subject will be discussed. Finally, a concise but comprehensive review of the different strategies that have been attempted to prevent the onset of antibody-mediated rejection is presented. These strategies encompass approaches aimed at interfering with the binding of xenoreactive antibodies with their targets, the use of conventional or novel immunosuppressants and splenectomy. It is undeniable that significant progress has been recently achieved in understanding the humoral rejection process of pig organs transplanted into primates. It is expected that a more comprehensive elucidation of the mechanisms underlying accommodation and tolerance may, in the not too distant future, further extend survival of pig organs transplanted into primates.

The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.

Given the ability of the B cell compartment to acquire tolerance to self we cannot explain why spontaneous humoral tolerance does not arise following transplantation. Here we review the fundamental mechanisms of B cell tolerance that operate in development and direct the reader to possible mechanisms that may explain how B cell tolerance fails to develop following transplantation