Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation

Abstract

Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This "immune-tolerance" liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat.

Keywords: Acute antibody-mediated rejection; C4d; Donor-specific anti-human leukocyte antigen antibodies; Human leukocyte antigen single antigen bead; Liver transplantation; Rejection; Solid-phase immunoassays.

Figure 1

Potential associations of donor-specific human leukocyte antigen antibodies with outcomes in liver transplant or simultaneous liver-kidney transplant recipients. No associations have been confirmed in large randomized controlled trials. Adapted from O'Leary et al[34]. HLA: Human leukocyte antigen; DSA: Donor-specific anti-HLA antibodies.

Figure 2

Idiopathic fibrosis progression. Hypothetical chain of events. DSA: Donor-specific anti-HLA antibodies; LT: Liver transplant.

Figure 3

Mechanisms involved in humoral graft damage. Early post transplantation after ischemia/reperfusion injury (a) the endothelium can release several chemokines and cytokines to gather innate immune cells as neutrophils, macrophages. In this inflammatory setting, the graft endothelium could be activated and expressed human leukocyte antigen (HLA) class-II antigens (b), subsequently, these antigens could be recognized by anti-HLA class-II antibodies. If the antibodies are able to fix complement factors could trigger classical complement pathway that finally induce the membrane attack complex (c) on targeted endothelial cells. During complement activation, C4a component is degraded in C4d and finally deposited on capillaries. After destruction of endothelial cells, the HLA class-II molecules could be released and directly detected by circulating anti-HLA antibodies that once recognized by FC receptors on NK cells could direct cytotoxic actions and cytokine production. Another potential mechanism of humoral graft damage could be driven by platelet activation and thrombi formation (e).