Antibody-mediated rejection: emergence of animal models to answer clinical questions

Abstract

Decades of experiments in small animals had tipped the balance of opinion away from antibodies as a cause of transplant rejection. However, clinical experience, especially with sensitized patients, has convinced basic immunologists of the need to develop models to investigate mechanisms underlying antibody-mediated rejection (AMR). This resurgent interest has resulted in several new rodent models to investigate antibody-mediated mechanisms of heart and renal allograft injury, but satisfactory models of chronic AMR remain more elusive. Nevertheless, these new studies have begun to reveal many insights into the molecular and pathological sequelae of antibody binding to the allograft endothelium. In addition, complement-independent and complement-dependent effects of antibodies on endothelial cells have been identified in vitro. As small animal models become better defined, it is anticipated that they will be more widely used to answer further questions concerning mechanisms of antibody-mediated tissue injury as well as to design therapeutic interventions.

Figure 1

Diagram of major antibody initiated processes, including antigen cross-linking, Fc receptor interaction and complement activation. Antigen cross-linking causes exocytosis of vWf, expression of adhesion molecules (such as P-selectin), release of growth factors, upregulation of receptors and cell proliferation. Leukocytes with Fc receptors (eg, neutrophils and macrophages) can be stimulated by antibodies bound to antigen. The strength of Fc receptor interactions with IgG is dependent on the carbohydrate side chains (yellow hexagons) on the antibodies. The carbohydrate side chains on IgG also interact with the first components of the classical and lectin complement pathways. The many split products of complement expand the effects of antibodies in part through complement receptors (CR) on leukocytes.