The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body’s immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.

Background. Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. Methods. Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. Results. The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. Conclusions. These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.

Mannose-binding lectin (MBL) is an activator of the lectin pathway of the C 0 system and hence an important component of the innate immune system. Although reports are conflicting, MBL deficiency has been reported to influence the infection susceptibility in hematology/ oncology patients or recipients of allogeneic hematopoietic SCT (HSCT). MBL levels and the occurrence of infections were retrospectively analyzed in 98 pediatric HSCT patients. MBL deficiency in recipients was not corrected by HSCT using a donor with normal MBL production. In addition, low serum MBL concentrations were not associated with increased susceptibility to any type of infections post-HSCT in this cohort of pediatric HSCT recipients.

Background: Deceased donor kidney offers are frequently declined multiple times before acceptance for transplantation, despite significant organ shortage and long waiting times. Whether the number of times a kidney has been declined, reflecting cumulative judgments of clinicians, is associated with long-term transplant outcomes remains unclear. Methods: In this national, retrospective cohort study of deceased donor kidney transplants in the United States from 2008 to 2015 (n=78,940), we compared donor and recipient characteristics and short- and long-term graft and patient survival outcomes grouping by the sequence number at which the kidney was accepted for transplantation. We compared outcomes for kidneys accepted within the first 7 offers in the match run, after 8-100 offers, and for hard-to-place kidneys distinguishing those requiring >100 and >1000 offers before acceptance. Results: Harder to place kidneys had lower donor quality and higher rates of delayed graft function (46% among kidneys requiring >1000 offers before acceptance versus 23% among kidneys with ≤7 offers). In unadjusted models, later sequence groups had higher hazard of all-cause graft failure, death-censored graft failure, and patient mortality; however, these associations were attenuated after adjusting for kidney donor risk index (KDRI). After adjusting for donor factors already taken into consideration during allocation and recipient factors associated with long-term outcomes, graft and patient survival outcomes were not significantly different for the hardest-to-place kidneys compared to the easiest-to-place kidneys, with the exception of death-censored graft failure (adjusted hazard ratio: 1.16, 95% CI: 1.05-1.28). Conclusions: Late sequence offers may represent missed opportunities for earlier successful transplant for the higher-priority waitlisted candidates for whom the offers were declined.

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The liver's capacity to grow in response to metabolic need is well known. However, long-term growth of liver allografts in pediatric recipients has not been characterized. A retrospective review of pediatric recipients at a single institution identified patients who had cross-sectional imaging at 1, 5, and 10 years post-transplant. Using volumetric calculations, liver allograft size was calculated and percent SLV were compared across the different time points; 18 patients ranging from 0.3 to 17.7 years old were identified that had imaging at 2 or more time points. Measured liver volumes increased by 59% after 5 years and 170% after 10 years. The measured liver volumes compared to calculated %SLV for these patients were 123 ± 37%, 97 ± 19%, and 118 ± 27% at 1, 5, and 10 years after transplant, respectively. Our data suggest that liver allografts in pediatric recipients increase along with overall growth, and reach SLVs for height and weight by 5 years post-transplantation. Additionally, as pediatric recipients grow, the livers appear to maintain appropriate SLV.

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