ABO-compatible liver allograft antibody-mediated rejection

Abstract

Purpose Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: 1) solid phase antibody testing enabled more precise antibody characterization; 2) increased expectations for long-term, morbidity-free survival; and 3) immunosuppression minimization trials. Recent Findings Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by DSA persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophage-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling and hepatocanalicular cholestasis often combined with T cell-mediated rejection (TCMR). Chronic AMR is less well-defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis is more difficult to identify than in acute AMR. Summary More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.

Five‐year histological and serological follow‐up of operationally tolerant pediatric liver transplant recipients enrolled in WISP‐R

“…In the quiescent, noninjured, noninflamed liver, class I antigens are constitutively expressed by all cells. The liver secretes class I HLA antigens that can bind to and neutralize circulating class I DSA to form immune complexes that are cleared by Kupffer cells (reviewed in Demetris et al). Preferential clearance of class I compared to class II DSA from the circulation has been reported after both liver transplantation alone and simultaneous liver and kidney transplantation .…”

Liver transplantation: Rejection and tolerance

“…Because of the liver's inherent ability to reduce the level of circulating DSA, as well as its unique regenerative capacity after a mild injury, most sensitized liver transplant recipients do not incur DSA‐mediated graft injury. In all, AMR of the liver is estimated to occur in <1% of all liver transplants and in approximately 5% of all sensitized liver recipients . The current Banff criteria for the diagnosis of acute AMR of the liver requires the following: Histological pattern of injury consistent with acute AMR (microvasculitis, portal edema, ductular reaction, and portal microvascular endothelial hypertrophy). Presence of DSA in the serum. Diffuse microvascular complement component 4d (C4d) deposition. Exclusion of other insults …”

The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives

“…Demetris et al have described two distinct histopathologic phenotypes associated with antibody-mediated rejection (AMR) in the liver graft, acute and chronic AMR [20]. Acute AMR is extraordinarily rare, occurring in less than 1% of all LT cases, and is almost exclusively limited to the first few weeks after transplantation in highly sensitized recipients [9, 21].…”

“…The clinical features of acute AMR resemble those seen with ABO-incompatible transplants and include allograft dysfunction, DSA persistence, refractory thrombocytopenia, and hypocomplementemia. Histopathologically, acute AMR is characterized by portal edema, endothelial cell hypertrophy, and eosinophilia within the portal microvasculature, hepatocyte swelling, ductular reaction, and cholestasis [20, 30]. These patterns of injury are analogous to findings indicative of capillaritis as seen with AMR of other solid organ allografts.…”