Acute Antibody-Mediated Liver Allograft Rejection
Many patients with low-to-moderate MFI Class I DSA have no apparent quantifiable consequences of DSA in the absence of recurrent disease, but the full spectrum of potential insults associated with some DSA has yet to be identified (Table 1). The concepts of acute AMR occurring early after transplantation and chronic (or indolent) AMR occurring late after transplant as broad categorizations of antibody-mediated injury are gaining traction in the literature. Although hyperacute rejection has been reported, the more common and most widely recognized presentation attributed to acute AMR is otherwise unexplained liver allograft dysfunction, falling platelet and complement levels and increased levels of circulating immune complexes in patients with preformed persistent DSA in whom liver biopsy shows microvascular injury in addition to other characteristics commonly associated with allograft rejection. This occurs most commonly during the first several weeks after transplantation and is seen in approximately 1% of all early (<90 days) liver allograft failures, but the rate increases to 10% of idiopathic early liver allograft failures in DSA-positive patients.
Animal models have provided insights into the relative resistance of the liver to acute antibody-mediated injury, as well as identification of factors that override these natural defense mechanisms. Mechanisms of resistance to acute antibody-mediated injury include: the large size and unconventional sinusoidal microvascular bed of the liver; secretion of high levels of soluble HLA antigens; Kupffer cell phagocytosis of immune complexes, platelet aggregates and activated complement components; the dual afferent circulation of the liver; a homologous complement source; and the ability of the liver to repair and regenerate after injury. Conversely, high-level sensitization; IgG antibodies, especially those subclasses that efficiently fix complement and mediate antibody-dependent cellular cytotoxicity (ADCC); reduced-size grafts; Kupffer cell inactivation or depletion; and antibody targeting of endothelial cell antigens all increase susceptibility to AMR-related injury. Acute AMR has been produced reliably in highly sensitized rats and confirmed in rhesus macaques. In the original rat model, antibody-mediated injury was characterized by congestion, edema and hemorrhage into the liver parenchyma and passive administration of HLA Class I antibodies, alone, in high titers was sufficient to cause injury. Revival of interest in animal models of liver allograft AMR will be essential to a better understanding of: (1) all the possible acute and chronic consequences of DSA and association of damage or accommodation with antibody class, subclass, MFI and specificity; (2) characteristics and timing of ADCC pathways; (3) endothelial physiologic consequences of antibody binding; and (4) potential novel therapeutic strategies.