Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future.

Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.

Successful Liver Transplantation from a Deceased Donor After Ethylene Glycol Ingestion: A Case Report and Review of the Literature of Organ Donation from Poisoned Donors.

Despite the increase in deceased organ donation over the past ten years, the gap between patients awaiting transplant and available organs continues to widen. Deceased donors secondary to acute fatal poisonings represent less than 1% of all organ donors. Organs from poisoned donors have largely been discarded due to concerns of toxin transmission and poor organ function as well as the paucity of data that exists regarding this donor population. Here, we report a case of a 40-year-old male who underwent successful liver re-transplantation from a donor who died following ethylene glycol ingestion. To our knowledge this case report is the first to describe successful re-transplantation from an ethylene glycol-poisoned donor. We also provide a comprehensive review of the literature describing organ donation from poisoned donors.

Belatacept Conversion in Kidney After Liver Transplantation.

BACKGROUND: Costimulatory blockade with belatacept has demonstrated long-term benefits in renal transplantation, but de novo use in liver transplant recipients has resulted in increased rejection, graft loss, and death. However, belatacept conversion as a calcineurin inhibitor (CNI) avoidance strategy has not been studied and may be of benefit in liver transplantation where CNI-induced renal dysfunction and toxicity are barriers to improved outcomes. METHODS: Using clinical data extracted from our institutional medical record, we report on 8 patients who underwent kidney after liver transplantation and were treated with belatacept-based immunosuppression and transient CNI therapy. RESULTS: All patients tolerated belatacept therapy without any patient deaths or graft losses. No episodes of rejection, de novo donor-specific antibody formation, or major systemic infections were observed, and all patients demonstrated preserved liver and excellent renal allograft function. Patients received belatacept for a median duration of 13.2 mo, and at a median follow-up of 15.9 mo post-kidney transplant, 6 of 8 patients continued on belatacept with 3 completely off and 3 poised to transition off CNI. CONCLUSIONS: These findings are the first evidence that in liver transplant recipients requiring subsequent kidney transplantation, belatacept-based therapy can potentially facilitate CNI-free maintenance immunosuppression. This supports the possibility of belatacept conversion in stand-alone liver transplant recipients as a viable method of CNI avoidance.

Biliary Complications Following Adult Deceased Donor Liver Transplantation: Risk Factors and Implications at a High-volume US Center.

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.

Adenovirus causing hepatic abscess formation and unexplained fever in adult liver transplant recipients.

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.

Blockade of BAFF Reshapes the Hepatic B Cell Receptor Repertoire and Attenuates Autoantibody Production in Cholestatic Liver Disease.

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.

A Mimic of Posttransplant Lymphoproliferative Disease Following Liver Transplant.

Generalized lymphadenopathy after organ transplant is a concerning finding, often indicating the devel-opment 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.

Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic γδ T-Cell Receptor-Positive Cells and Pathogenesis of Cholestatic Liver Disease.

BACKGROUND & AIMS: Variants at the ABCB4 or MDR2 locus, which encodes a biliary transport protein, are associated with a spectrum of cholestatic liver diseases. Exacerbation of liver disease has been linked to increased hepatic levels of interleukin (IL) 17, yet the mechanisms of this increase are not understood. We studied mice with disruption of Mdr2 to determine how defects in liver and alteration in the microbiota contribute to production of IL17 by intrahepatic γδ T cells. METHODS: We performed studies with Mdr2-/- and littermate FVB/NJ (control) mice. IL17 was measured in serum samples by an enzyme-linked immunosorbent assay. Mice were injected with neutralizing antibodies against the γδ T-cell receptor (TCR; anti-γδ TCR) or mouse IL17A (anti-IL17A). Livers were collected and bacteria were identified in homogenates by culture procedures; TCRγδ+ cells were isolated by flow cytometry. Fecal samples were collected from mice and analyzed by 16S ribosomal DNA sequencing. Cells were stimulated with antibodies or bacteria, and cytokine production was measured. We obtained tissues from 10 patients undergoing liver transplantation for primary sclerosing cholangitis or chronic hepatitis C virus infection. Tissues were analyzed for cytokine production by γδ TCR+ cells. RESULTS: Mdr2-/- mice had collagen deposition around hepatic bile ducts and periportal-bridging fibrosis with influx of inflammatory cells and increased serum levels of IL17 compared with control mice. Administration of anti-IL17A reduced hepatic fibrosis. Livers from Mdr2-/- mice had increased numbers of IL17A+ γδTCR+ cells-particularly of IL17A+ Vγ6Jγ1 γδ TCR+ cells. Fecal samples from Mdr2-/- mice were enriched in Lactobacillus, and liver tissues were enriched in Lactobacillus gasseri compared with control mice. Mdr2-/- mice also had increased intestinal permeability. The γδ TCR+ cells isolated from Mdr2-/- livers produced IL17 in response to heat-killed L gasseri. Intraperitoneal injection of control mice with L gasseri led to increased serum levels of IL17 and liver infiltration by inflammatory cells; injection of these mice with anti-γδ TCR reduced serum level of IL17. Intravenous injections of Mdr2-/- mice with anti-γδ TCR reduced fibrosis; liver levels of IL17, and inflammatory cells; and serum levels of IL17. γδTCR+ cells isolated from livers of patients with primary sclerosing cholangitis, but not hepatitis C virus infection, produced IL17. CONCLUSIONS: In Mdr2-/- mice, we found development of liver fibrosis and inflammation to require hepatic activation of γδ TCR+ cells and production of IL17 mediated by exposure to L gasseri. This pathway appears to contribute to development of cholestatic liver disease in patients.

Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection.

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.

Nonhuman primate models of transplant tolerance: closer to the holy grail.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Hepatic hydatid cyst: a rare cause of recurrent pancreatitis.

A case of pancreatitis secondary to a hepatic hydatid cyst is illustrated together with its preoperative imaging and intraoperative appearance. Cystobiliary communication is a common complication of large hydatid cysts, and episodes of recurrent pancreatitis resulting from passage of cyst contents down the biliary tract are rarely described. The clinical manifestations, diagnostic workup, and surgical management options of echinococcal-related pancreatitis are discussed, and a review of the literature is provided.

Hepatic retransplant: what have we learned?

Hepatic retransplant accounts for 5% to 15% of liver transplants in most series and is associated with significantly increased hospital costs and inferior patient survival when compared with primary liver transplant. Early retransplants are usually due to primary graft nonfunction or vascular thrombosis, whereas later retransplants are most commonly necessitated by chronic rejection or recurrent primary liver disease. Hepatic retransplant remains the sole option for survival in many patients facing allograft failure after liver transplant. With improved techniques to match retransplant candidates with appropriate donor grafts, it is hoped that the outcomes of retransplant will continue to improve in future.

Combined costimulatory and leukocyte functional antigen-1 blockade prevents transplant rejection mediated by heterologous immune memory alloresponses.

BACKGROUND: Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection crossreact with donor antigens. Because of their diminished requirements for costimulation during recall, these pathogen-elicited allocrossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy. METHODS: We used an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor. RESULTS: We demonstrate that coupling the integrin antagonist anti-leukocyte functional antigen (LFA)-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP³âº Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone. CONCLUSIONS: As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials.

Protein S deficiency in a living liver donor.

Protein S deficiency is a thrombophilia associated with increased risk of thromboembolic episodes in affected patients. Traditionally, protein S deficiency in a potential donor was considered an absolute contraindication to living donor liver transplantation, both due to the increased risk incurred by the thrombophilic donor as well as the risk of transmitting the thrombophilia to the liver recipient, as protein S is predominantly produced by the liver. We present the first successful case of living donor liver transplantation using a donor with asymptomatic protein S deficiency. Interestingly, whereas the donor continued to have protein S levels approximately 50% of normal, the recipient maintained normal levels of protein S post-transplant, potentially due to compensation by extra-hepatic protein S production. We discuss the prior literature of protein S deficiency acquired via liver transplantation, and we evaluate potential criteria by which the safety of transplants utilizing this pool of donors may be enhanced.

Domino liver transplantation: indications, techniques, and outcomes.

The long-term shortage of livers available for transplantation has spurred the development of many strategies to bolster the donor organ supply. One particularly innovative strategy is domino liver transplantation in which a select group of liver transplant recipients can donate their explanted native livers for use as liver grafts in other patients. Several hereditary metabolic diseases (such as familial amyloid polyneuropathy, maple syrup urine disease, and familial hypercholesterolemia) are caused by aberrant or deficient protein production in the liver, and these conditions can be cured with an orthotopic liver transplant. Although their native livers eventually caused severe systemic disease in these patients, these livers are otherwise structurally and functionally normal, and they have been used successfully in domino liver transplants for the past 15 years. This article will review the indications for donating or receiving a domino liver transplant, the surgical techniques necessary to perform these transplants, as well as the recently revealed long-term outcomes and risks of domino transplantation.

Partial abdominal evisceration and intestinal autotransplantation to resect a mesenteric carcinoid tumor.

BACKGROUND: Midgut carcinoids are neuroendocrine tumors that commonly metastasize to the intestinal mesentery, where they predispose to intestinal obstruction, ischemia and/or congestion. Because of their location, many mesenteric carcinoid tumors are deemed unresectable due to the risk of uncontrollable bleeding and prolonged intestinal ischemia. CASE PRESENTATION: We report the case of a 60-year-old male with a mesenteric carcinoid tumor obstructing his superior mesenteric vein, resulting in intestinal varices and severe recurrent GI bleeds. While his tumor was thought to be unresectable by conventional techniques, it was successfully resected using intestinal autotransplantation to safely gain access to the tumor. This case is the first described application of this technique to carcinoid tumors. CONCLUSIONS: Intestinal autotransplantation can be utilized to safely resect mesenteric carcinoid tumors from patients who were not previously thought to be surgical candidates. We review the literature concerning both carcinoid metastases to the intestinal mesentery and the use of intestinal autotransplantation to treat lesions involving the mesenteric root.

Limiting the amount and duration of antigen exposure during priming increases memory T cell requirement for costimulation during recall.

Donor-reactive memory T cells (Tmem) can play an important role in mediating graft rejection after transplantation. Transplant recipients acquire donor-reactive Tmem not only through prior sensitization with alloantigens but also through previous exposure to environmental pathogens that are cross-reactive with allogeneic peptide-MHC complexes. Current dogma suggests that most, if not all, Tmem responses are independent of the requirement for CD28 and/or CD154/CD40-mediated costimulation to mount a recall response. However, heterogeneity among Tmem is increasingly being appreciated, and one important factor known to impact the function and phenotype of Ag-specific T cell responses is the amount/duration of Ag exposure. Importantly, the impact of Ag exposure on development of costimulation independence is currently unknown. In this study, we interrogated the effect of decreased Ag amount/duration during priming on the ability of donor-reactive Tmem to mediate costimulation blockade-resistant rejection during a recall response after transplantation in a murine model. Recipients possessing donor-reactive Tmem responses that were generated under conditions of reduced Ag exposure exhibited similar frequencies of Ag-specific T cells at day 30 postinfection, but, strikingly, failed to mediate costimulation blockade-resistant rejection after challenge with an OVA-expressing skin graft. Thus, these data demonstrate the amount/duration of Ag exposure is a critical factor in determining Tmem's relative requirement for costimulation during the recall response after transplantation.

The changing role of natural killer cells in solid organ rejection and tolerance.

Natural killer (NK) cells have emerged as a particular focus of interest in transplantation due to their ability to distinguish allogeneic major histocompatibility complex (MHC) antigens and their potent cytolytic effector mechanisms. Once relegated to the field of bone marrow transplantation, NK cells have recently been shown to participate in the immune response against solid organ allo- and xenografts. These new findings suggest that the role of NK cells in solid organ rejection and tolerance needs to be reexamined.