Antibody-mediated Rejection - an Ounce of Prevention is Worth a Pound of Cure

07:10: Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity

William M. Baldwin III, Lerner Research Institute, Cleveland, USA

In transplantation, activation of complement has generally been equated to antibody-mediated rejection, but complement is also important in recognition of apoptotic and necrotic cells as well as in modifying antigen presentation to T cells and B cells.

Antibodies are very effective activators of complement through the classical and the lectin pathways by binding C1 and mannose binding lectin (MBL), respectively. Several variables determine the capacity of antibodies to activate complement including their concentration, isotype, and carbohydrate side chain structure. Low levels of complement activation can be modulated by tissue-bound and circulating regulators of complement. These include decay accelerating factor (DAF; CD55), membrane co-factor protein (MCP; CD46) and factor I, all of which can limit C3 activation. Activation of C3 is a critical step because the split product C3b amplifies the complement cascade through the alternative pathway, which serves as a positive feedback loop. Very high levels of alloantibodies can overwhelm the regulatory molecules and cause lysis of endothelial cells. This occurs in hyperacute rejection. It also occurs in xenografts because the incompatible regulatory molecules are less effective. Short of lysis, the biological split products resulting from complement activation orchestrate vasculitis. Soluble split products (e.g. C3a and C5a) chemoattract and activate granulocytes and macrophages, while tissue-bound complement components (C1q, C4b, and C3b) target the attachment of leukocytes. Consequently, marginated neutrophils and macrophages typify antibody-mediated rejection. When antibody binds to the vascular endothelium, plasma provides abundant complement that is primarily produced in the liver

Complement produced by macrophages and epithelial cells in the transplant can also modulate allorecognition and rejection. This process involves mechanisms that evolved before adaptive immunity. Primitive species with no adaptive immune system have homologues of C1, MBL and C3. These proteins bind to pathogens and injured tissue marking them for phagocytosis. In mammals, phagocytic cells, particularly macrophages, produce all the components of the complement cascade and they have receptors for activated complement components. As a result, macrophages and granulocytes respond rapidly to apoptotic and necrotic tissues. These mechanisms are elicited when organs sustain tissue injury from brain death, prolonged life support, ischemia, and reperfusion. The effects of complement on granulocytes and macrophages can determine the direction and magnitude of the subsequent adaptive responses. During antigen presentation, C3 and C5 produced by macrophages and dendritic cells can also stimulate T cells through C3a and C5a receptors. T cells express DAF that regulates this source of stimulation.Small animal models have been developed to test the role of complement in transplantation.

Clinical findings continue to be the standard for evaluating experimental models because there are significant differences between the rodent and human complement systems.

William M. Baldwin III

Dr. Baldwin received his Ph.D. and his M.D. from the University of Rochester in 1973 and 1975, respectively. He completed a residency in Pathology at the Peter Bent Brigham (now Brigham and Women’s) Hospital. His interests in transplantation were enhanced at the Peter Bent Brigham Hospital, where Drs. Dammin (Pathology), Merrill (Nephrology) and Murray (Surgery), who were members of the team that performed the first successful renal transplant, were still active. A fellowship at The Academic Hospital in Leiden, The Netherlands, where Eurotransplant is centered, gave him experience in tissue typing, antibody assessment and complement biology. His research in these areas continued to evolve as a faculty member at Duke and then at Johns Hopkins. He has been involved in the training of basic and clinical scientists at many stages of their careers. His involvement in Program Projects over the years as Principal Investigator, Project Leader and Core Leader have established collaborative interactions with both basic scientists and clinicians. He has published over 100 peer-reviewed articles and over 40 review articles or book chapters on transplantation immunology. His research uses clinical insights to develop clinically relevant models of organ transplantation in rats and mice. His research focuses on the modulation of adaptive immune responses by components of innate immunity. The current goal of his studies is to understand the mechanisms through which antibodies and complement alter lymphocyte responses at the level of endothelial cells, platelets and leukocytes. These mechanisms have general relevance to vascular pathology as well as transplantation. Dr. Baldwin is a member of the American Association of Immunologists, the Transplantation Society and the American Society of Transplant Physicians. He serves on the editorial board of Transplantation and is an Associate Editor of the Journal of Immunology and the American Journal of Transplantation.