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Late Humoral Rejection in a Compliant ABO-compatible Liver Transplant Recipient

Wilson, Colin H.; Agarwal, Kosh; Talbot, David; Jaques, Brian C.; Manas, Derek M.; Carter, Vaughan; Burt, Alastair D.; Hübscher, Stefan

Author Information
doi: 10.1097/01.tp.0000229939.85412.27

Humoral rejection (HR) is an immunological complication of solid organ transplantation but whose role in liver transplantation (LT) is debated. We present a case that fulfils all of the criteria required for the diagnosis of HR: donor-specific antibody (DSA), C4d deposition, tissue pathology, and evidence of organ dysfunction (1).

In March 2001, a 36-year-old female was transplanted for fulminant seronegative liver failure, receiving a blood-group matched whole deceased donor graft from a 20-year-old donor. Initial immunosuppression was with tacrolimus-based triple therapy (azathioprine 75 mg and prednisone 20 mg). Her postoperative course over three years was unremarkable and, as she was overtly compliant with tacrolimus, the azathioprine was reduced and steroids stopped.

Four years postLT, she was admitted to a local hospital with itch and clinical jaundice. Liver biopsy demonstrated acute severe rejection with a tacrolimus level of 7.9 ng/dl (Fig. 1, biopsy 1). Mycophenolate mofetil (2 g/day) and oral steroids were commenced. On admission to our institution liver biochemistry continued to deteriorate (day 1 bilirubin 181, alanine aminotransferase [ALT] 1267, alkaline phosphate 333; Figure 1) and bolus methylprednisone (500 mg iv bd) was instituted without biochemical response. Repeat liver biopsy demonstrated ongoing moderate cellular rejection, bile duct atypia but no evidence of bile duct loss (biopsy 2). Despite further steroid augmentation, no improvement was seen (biopsy 3). Human leukocyte antigen (HLA) antibody testing performed using Luminex technology identified an allogenic donor specific HLA-DR52 antibody, which was not present peri-LT.

FIGURE 1.
FIGURE 1.:
The response of liver function tests (LFTs) to therapy. On admission (day 1, December 2006), LFTs were significantly deranged compared with December 2004. Class II HLA antibody titers (median fluorescence index), alkaline phosphatase (Alk Phos, iu/l), alanine aminotransferase (ALT, iu/l), bilirubin (μmol/L). In March 2006 (one month after discharge), LFTs were stable. Arrows or boxes represent treatments given. Numbers represent biopsies. Biopsy 1: Severe acute cellular rejection (ACR) (+++) with bile duct atypia (BDA). Biopsy 2: moderate ACR (++) with BDA, no sign of ductopenia. Biopsy 3: persistent moderate ACR (++), centrilobular necro-inflammation (CNI), no evidence of bile duct loss. Biopsy 4: mild ACR (+), BDA and CNI improved. Biopsy 5: ACR resolved, BDA and CNI not seen.

Further treatment with plasmapheresis, intravenous immunoglobulins and rituximab produced a significant transient biochemical response, but no histological change (biopsy 4) and biochemical rebound after seven days. However, antithymocyte globulin (ATG) induced a sustained biochemical improvement and a significant reduction in the inflammatory infiltrate. At review and rebiopsy, a month later, the patient was clinically well, the HLA-DR52 antibody was absent and the cellular rejection had resolved (biopsy 5). Retrospective immunostaining of three biopsies was positive for C4d in small portal vessels and no class I, auto, or viral antibodies were detected on serology.

Late HR is uncommon (approx. 5% [2]) and has been associated with previous rejection episodes (2) and noncompliance (3). Humoral mechanisms have been implicated in the pathogenesis of bile duct loss and arteriopathy in chronic rejection (4). Some histological features of chronic rejection were seen in this case (Fig. 1, bile duct atypia and centrilobular necroinflammation); however, ductopenia was not seen and the graft dysfunction was successfully reversed.

Rituximab and plasmapheresis have proven to be effective in the prevention and treatment of early HR associated with DSA against ABO antigens (5, 6). These naturally occurring immunoglobulin M antibodies are produced by T-cell-independent B1 cells (7). In our case, the HLA class II specific DSA only showed a lasting response to a combination of therapies targeting multiple arms of the specific immune system, suggesting this HR was “driven” by activated alloreactive T-cells. Late rejection in LT, unlike other organs, is not invariably associated with a poor prognosis after successful treatment (2, 3) and the outlook for this patient is hopeful.

Colin H. Wilson

Kosh Agarwal

David Talbot

Brian C. Jaques

Derek M. Manas

The Liver Transplant Unit

The Freeman Hospital

Newcastle-upon-Tyne, United Kingdom

Vaughan Carter

Tissue Typing Laboratory

National Health Service Blood and Transplant

Newcastle-upon-Tyne, United Kingdom

Alastair D. Burt

The Department of Histopathology

Royal Victoria Infirmary

Newcastle-upon-Tyne, United Kingdom

Stefan Hübscher

Department of Pathology

University of Birmingham

Birmingham, United Kingdom

REFERENCES

1. Takemoto SK, Zeevi A, Feng S, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004; 4: 1033.
2. Junge G, Tullius SG, Klitzing V, et al. The influence of late acute rejection episodes on long-term graft outcome after liver transplantation. Transplant Proc 2005; 37: 1716.
3. Mor E, Gonwa TA, Husberg BS, et al. Late-onset acute rejection in orthotopic liver transplantation–associated risk factors and outcome. Transplantation 1992; 54: 821.
4. Batts KP, Moore SB, Perkins JD, et al. Influence of positive lymphocyte crossmatch and HLA mismatching on vanishing bile duct syndrome in human liver allografts. Transplantation 1988; 45: 376.
5. Usuda M, Fujimori K, Koyamada N, et al. Successful use of anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible living-related liver transplantation. Transplantation 2005; 79: 12.
6. Kawagishi N, Satoh K, Enomoto Y, et al. New strategy for ABO-incompatible living donor liver transplantation with anti-CD20 antibody (rituximab) and plasma exchange. Transplant Proc 2005; 37: 1205.
7. Kay LA. Cellular basis of immune response to antigens of ABO blood-group system. Capacity to provide help during response to T-cell-dependent ABO-system antigens is restricted to individuals of blood group O. Lancet 1984; 2: 1369.
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