Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

The impact of donor‐specific HLA alloantibodies (DSA) on short‐ and long‐term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody‐mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody‐mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell–mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver–kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under‐appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

Early and late AMR exhibit distinct immunologic characteristics and respond differently to PI therapy.

The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single-antigen beads. Fifty-two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow-up was 27.0 ± 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA >20% (current) and/or >50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6-fold increased allograft loss risk, p = 0.017) to be significant. Four-year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/ C4d) (65%) or antibody-mediated rejection (35%) (p < 0.001). Patients with >50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.

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Reactivation of the polyomavirus BK (BKV) causes polyomavirus nephropathy (PVN) in kidney transplant(KTx) recipients and may lead to loss of the renal allograft. We have identified two HLA-A*0201-restricted nine-amino-acid cytotoxic T lymphocyte (CTL) epitopes of the BKV major capsid protein VP1, VP1 p44 , and VP1 p108. Using tetramer staining assays, we showed that these epitopes were recognized by CTLs in 8 of 10 (VP1 p44 ) and 5 of 10 (VP1 p108 ) HLA-A*0201 ؉ healthy individuals, while both epitopes elicited a CTL response in 10 of 10 KTx recipients with biopsy-proven PVN, although at variable levels. After in vitro stimulation with the respective peptides, CTLs directed against VP1 p44 were more abundant than against VP1 p108 in most healthy individuals, while the converse was true in KTx recipients with PVN, suggesting a shift in epitope immunodominance in the setting of active BKV infection. A strong CTL response in KTx recipients with PVN appeared to be associated with decreased BK viral load in blood and urine and low anti-BKV antibody titers, while a low or undetectable CTL response correlated with viral persistence and high anti-BKV antibody titers. These results suggest that this cellular immune response is present in most BKV-seropositive healthy individuals and plays an important role in the containment of BKV in KTx recipients with PVN. Interestingly, the BKV CTL epitopes bear striking homology with the recently described CTL epitopes of the other human polyomavirus JC (JCV), JCV VP1 p36 and VP1 p100 . A high degree of epitope cross-recognition was present between BKV and corresponding JCV-specific CTLs, which indicates that the same population of cells is functionally effective against these two closely related viruses.BK virus (BKV) is the etiologic agent of polyomavirus nephropathy (PVN), an infection of the kidney occurring in up to 8% of kidney transplant (KTx) recipients (38). BKV infects 90% of adults (20) but does not cause any disease in healthy individuals. Viral reactivation in renal transplant recipients occurs in the setting of pharmacologic immunosuppression. This reactivation leads to a lytic infection of renal tubular epithelial cells of the transplanted kidney, which was responsible for renal allograft loss in as high as 45 to 67% of cases in early experiences and is currently responsible for 10 to 30% of renal allograft losses (29,35,38). There is no specific antiviral treatment for PVN. Therefore, this disease is a growing medical problem as the population of KTx recipients continues to increase. The only currently available therapeutic option for PVN consists of reduction of chemical immunosuppression, which allows reconstitution of the immune system to clear the virus (4) but which may also be associated with an increased risk of transplant rejection. Hence, prognostic markers of disease evolution and a better understanding of the immune response against BKV are urgently needed for the appropriate management of patients with PVN.BKV has 75% homology with JC virus (JCV), the cau...

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P<0.0005 vs. reduced graft and < 0.03 vs. other LDLT groups). The incidence of late portal vein stenosis or thrombosis was significantly higher in the LDLT Group 2, (51%) than any of the other groups (LDLT 1, 16%; LDLT Group 3, 9%; RLT 4%;P<0.005 vs. cadaveric and < 0.02 vs. LDLT Group 1 and LDLT Group 3). Five year arterial graft and patient survival for patients who have experienced portal vein thrombosis or stenosis is 61% and 67%, respectively, versus 67% and 71% for those patients who have not experienced portal vein pathology, P=ns. Based on this experience, we recommend avoiding the use of cryopreserved iliac vein for portal vein reconstruction in liver transplantation. Every effort should be taken to eliminate the need for venous conduits in liver transplantation. If venous conduits must be utilized, cryopreserved femoral veins seem to provide superior patency rates. Careful clinical and ultrasonopraphic monitoring of patients at high risk for late venous thrombosis permits therapy with excellent graft and patient survival.