Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation (OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation (LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where long-term graft survival is observed on a regular basis and, hence, the liver has been deemed an immune-privileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.
BackgroundDistal cholangiocarcinoma (DCC) is a rare but over the last decade increasing malignancy and is associated with poor prognosis. According to the present knowledge curative surgery is the only chance for long term survival. This study was performed to evaluate prognostic factors for the outcome of patients undergoing curative surgery for distal cholangiocarcinoma.Methods75 patients who underwent surgery between January 2000 and December 2014 for DCC in curative intention were analysed retrospectively. Potential prognostic factors for survival were investigated including the extent of surgery using purposeful selection of covariates in multivariable Cox regression modeling.ResultsPreoperative biliary stenting (Hazard ratio (HR): 2.530; 95%-CI: 1.146–6.464, p = 0.020), the extent of surgery in case of positive histological venous invasion (HR: 1.209; 95%-CI: 1.017–1.410, p = 0.032), lymph node staging (HR: 2.183; 95%-CI: 1.250–3.841, p = 0.006), perineural invasion (HR: 2.118; 95%-CI: 1.147–4.054, p = 0.016) and postoperative complications graded in points according to Clavien-Dindo (HR: 1.395; 95%-CI: 1.148–1.699, p = 0.001) were indentified as independent significant risk factors for survival. Patients receiving preoperative biliary stenting showed prolonged duration between onset of symptoms and date of operation (p = 0.048).ConclusionsPreoperative biliary stenting reduces survival possibly due to delayed surgery. The extent of surgery is not an independent risk factor for survival except for patients with concomitant histological venous invasion. Oncological factors and postoperative surgical complications are independent prognostic factors for survival.
Hepatocyte transplantation is a promising therapeutic approach for various liver diseases. Despite the liver's tolerogenic potential, early immune‐mediated loss of transplanted cells is observed, and longterm acceptance has not been achieved yet. Patients deemed tolerant after liver transplantation presented an increased frequency of regulatory T cells (Tregs), which therefore also might enable reduction of posttransplant cell loss and enhance longterm allograft acceptance. We hence characterized hepatocyte‐induced immune reactions and evaluated the immunomodulatory potential of Tregs applying mixed lymphocyte cultures and mixed lymphocyte hepatocyte cultures. These were set up using peripheral blood mononuclear cells and primary human hepatocytes, respectively. Polyclonally expanded CD4+CD25highCD127low Tregs were added to cocultures in single‐/trans‐well setups with/without supplementation of anti‐interferon γ (IFNγ) antibodies. Hepatocyte‐induced alloresponses were then analyzed by multicolor flow cytometry. Measurements indicated that T cell response upon stimulation was associated with IFNγ‐induced major histocompatibility complex (MHC) class II up‐regulation on hepatocytes and mediated by CD4+ T cells. An indirect route of antigen presentation could be ruled out by use of fragmented hepatocytes and culture supernatants of hepatocytes. Allospecific proliferation was accompanied by inflammatory cytokine secretion. CD8+ T cells showed early up‐regulation of CD69 despite lack of cell proliferation in the course of coculture. Supplementation of Tregs effectively abrogated hepatocyte‐induced alloresponses and was primarily cell contact dependent. In conclusion, human hepatocytes induce a CD4+ T cell alloresponse in vitro, which is associated with MHC class II up‐regulation on hepatocytes and is susceptible to suppression by Tregs. Liver Transplantation 24 407–419 2018 AASLD.
Ante situm liver resection can be applied without cold perfusion nor veno-venous bypass with acceptable morbidity and mortality. However, this procedure remains challenging even for the experienced hepato-pancreato-biliary surgeon.
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