William H. Kitchens

Background.: Biliary leaks and anastomotic strictures comprise the majority of biliary complications (BCs) following liver transplantation (LT). Currently, there are few large contemporary case series of BCs in adult deceased donor liver transplant (DDLT) recipients in the literature. The purpose of this study was to examine the pretransplant and intraoperative risk factors associated with BCs at a high-volume tertiary care center and determine the impact of these BCs on their posttransplant course and long-term transplant outcomes. Methods.: We retrospectively reviewed all adult patients undergoing a DDLT from a donor after brain death (DBD) at Emory University between January 2015 and December 2019. Results.: A total of 647 adult patients underwent DDLT from a DBD during the study period and were included in analyses. The median length of follow-up posttransplant was 2.5 y. There were a total of 27 bile leaks (4.2%) and 69 biliary strictures (10.7%). Recipient age and cold ischemic time were identified as risk factors for biliary leak, whereas alcoholic cirrhosis as transplant indication was a risk factor for biliary stricture. Placement of a biliary stent was associated with the development of both biliary leaks and anastomotic strictures. Posttransplant, biliary leaks were a significant risk factor for future episodes of acute rejection but did not impact overall survival. In contrast, biliary strictures were associated with a significantly reduced overall survival at 1- and 4-y post DDLT. Conclusions.: BCs are a major source of morbidity and mortality following DDLT, with strictures and leaks associated with distinct posttransplant complications.

Generalized lymphadenopathy after organ transplant is a concerning finding, often indicating the development of lymphoma. We describe a 52-year-old liver transplant recipient who had clinical symptoms and imaging concerning for posttransplant lymphoproliferative disease. However, histologic evaluation of a lymph node biopsy revealed that the patient actually had a much rarer but relatively benign condition, Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis). We discuss the epidemiology, clinical symptoms, diagnosis, histologic features, and treatment of this uncommon mimic of posttransplant lymphoproliferative disease.

Adenovirus infection is commonly associated with self‐limited respiratory and gastrointestinal illnesses. However, infection in immunocompromised individuals, such as transplant recipients, can cause severe life‐threatening illness including pneumonitis, hemorrhagic cystitis, nephritis, hepatitis, and enterocolitis. In orthotopic liver transplant recipients, adenovirus viremia can cause hepatitis leading to marked transaminitis, allograft loss, and death. Although hepatic abscesses mediated by adenovirus have been described in other immunosuppressed patient populations, it has very rarely been described in liver transplant recipients. Here, we report two adult cases of hepatic abscesses following liver transplantation secondary to adenovirus infection and describe the successful treatment of these patients. Adenovirus should be considered as an uncommon etiology of hepatic abscess and unexplained fevers in adults following liver transplantation.

Defects in biliary transport proteins, MDR3 in humans and Mdr2 in mice, can lead to a spectrum of cholestatic liver disorders. Although B cell disorders and the aberrant Ab production are the leading extrahepatic manifestations of cholestatic liver diseases, the mechanism underlying this phenomenon is incompletely understood. Using mice with deficiency of Mdr2 that progressively develop cholestatic liver disease, we investigated the contributions of BAFF to aberrant IgG autoantibody production and hepatic fibrosis. In Mdr2−/− mice, hepatic B lymphocytes constitutively produced IgG during fibrosis progression, which correlated with elevated serum levels of BAFF, antinuclear Abs (ANA) and immune complexes. The elevated BAFF and ANA titers were also detected in human patients with primary sclerosing cholangitis and hepatobiliary cholangiopathies. Consistent with the higher BAFF levels, liver-specific selection of the focused BCR IgH repertoire was found on hepatic B cells in Mdr2−/− mice. Interestingly, the administration of anti-BAFF mAb in Mdr2−/− mice altered the BCR repertoire on hepatic B lymphocytes and resulted in reduced ANA and immune complex titers. However, anti-BAFF treatment did not attenuate hepatic fibrosis as measured by collagen deposition, hepatic expressions of collagen-1a, α-smooth muscle actin, and mononuclear cell infiltration (CD11b+ Ly-6chi monocytes and CD11b+ Gr1+ neutrophils). Importantly, depletion of B cells by anti-CD20 mAb reduced both hepatic fibrosis and serum levels of ANA and immune complexes. Our findings implicate B cells as the potential therapeutic targets for hepatic fibrosis and targeting BAFF specifically for attenuating the autoantibody production associated with cholestatic liver disease.

The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade–resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target. We next sought to improve the clinical efficacy of traditional costimulation blockade using belatacept by coupling it with anti-OX40L. Using a murine transplant model, we demonstrate that combined blockade enhances the suppression of alloreactive T cell proliferation and effector functions including both cytokine release and cytotoxic degranulation. We also show that anti-OX40L may be particularly useful in targeting alloreactive memory T cell responses that are relatively unaffected by traditional costimulation blockade regimens. Finally, we translated this therapy to a clinically relevant nonhuman primate renal transplant model, validating the efficacy of this regimen in a potentially novel steroid- and calcineurin inhibitor–free immunosuppression regimen.

Transplantation tolerance, successful acceptance of an organ without the perils of immunosuppression, has been a central goal of transplant research. Many strategies to achieve this tolerance have been examined over the past three decades, culminating in several human trials of transplant tolerance. This progression from the 'benchtop to the clinic' has depended on the successful implementation of these tolerance strategies in nonhuman primates. This review will examine the described methods of transplant tolerance induction in nonhuman primates. Although costimulatory blockade and mixed chimerism have an established record of achieving transplant tolerance in nonhuman primates, some of the most innovative recent techniques of tolerance induction have relied on cellular transfer. This review will fully examine the role of regulatory T-cell transfer and the use of mesenchymal stem/stromal cells to promote tolerance of organ allografts in nonhuman primates. Use of translational nonhuman primate transplant models is a vital intermediate step to advance new approaches of transplant tolerance induction from the lab to the clinic. This review will explore numerous techniques of tolerance induction that have been piloted in primates, including depletional techniques, induction of mixed hematopoietic chimerism, costimulation blockade, and adoptive transfer of tolerogenic cell populations.