Decrease of CD4+CD25+ T cells in peripheral blood after liver transplantation: association with immunosuppression.

CD25 (IL-2 receptor alpha-chain) marks a population of CD4-positive T cells with a suppressor phenotype. These CD4+CD25+ regulatory T cells can suppress both effector T cells and antigen-presenting cells and have been identified as a principle regulator of tolerance in experimental transplantation models. In the setting of human liver transplantation, however, little is known about the dynamics of these cells in relation to rejection, tolerance, and immunosuppression.

Human liver myeloid dendritic cells maturate in vivo into effector DC with a poor allogeneic T-cell stimulatory capacity.

We hypothesized that the relatively low immunogenicity of liver grafts might be related to a special maturation program of hepatic myeloid dendritic cells (MDC), yielding relatively immature effector MDC with weak allogeneic T-cell stimulatory capacity. To investigate whether maturation of human liver-derived MDC in vivo differs from maturation of MDC at another anatomical location, we compared the immunophenotypes and allogeneic T-cell stimulatory capacity of MDC from hepatic with those from inguinal lymph nodes (LN). MDC were purified by immunomagnetic selection from hepatic LN obtained from multi-organ donors (n = 8) and from inguinal LN of kidney transplant recipients (n = 7).

Heterotopic vs. orthotopic liver transplantation for chronic liver disease: a case-control comparison of short-term and long-term outcomes.

Between 1986 and 1990 we performed heterotopic liver transplantation (HLT) in 17 patients with chronic liver disease. In spite of theoretical advantages and favorable short-term results, we abandoned HLT because of doubts about the long-term outcome and the improved results of standard orthotopic liver transplantation (OLT). There are, however, no studies comparing the long-term survival after HLT and OLT for chronic liver disease.

Strain-specific in vitro cytokine production profiles do not predict rat liver allograft survival.

The aim of this study was to assess whether differences in cytokine production between inbred rat strains could explain differences in liver allograft survival. Splenocytes from five different strains were cultured with Concanavalin A to determine in vitro cytokine production profiles. Strain-specific TNF-alpha, IFN-gamma, IL-6 and IL-10 responses in naive animals were not associated with survival after rat liver transplantation.

Cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis.

In the field of liver transplantation, 7 reports have been published investigating the association between polymorphisms in cytokine genes and the occurrence of acute rejection in liver graft recipients. However, most of the individual studies lack the statistical power to detect a small-to-moderate effect of cytokine gene polymorphisms on the acute rejection rate. To overcome this problem, we performed a quantitative meta-analysis of 7 gene-association studies that were comparable with regard to definition of acute rejection and the type of immunosuppression used.

The transplanted liver graft is capable of clearing asymmetric dimethylarginine.

Asymmetric dimethylarginine (ADMA) has been recognized as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. Its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. Considering the liver as a crucial organ in the clearing of ADMA, we hypothesized increased ADMA levels during hepatic failure and, consequently, a decline of ADMA concentrations after successful liver transplantation.

The relative importance of cyclosporine exposure in heart, kidney or liver transplant recipients on maintenance therapy.

We investigated the relationship between cyclosporine exposure and the presence of cyclosporine-related side effects and assessed the advantage of the cyclosporine concentration 2 h post-dose (C(2)) over pre-dose concentration (C(0)) monitoring. Cyclosporine area-under-the-concentration-time curves were measured during the absorption phase (AUC(0-4 h)) in 49 liver, 28 heart and 26 kidney transplant recipients (time since transplantation >6 years) with or without cyclosporine-related side effects on maintenance therapy. The cyclosporine C(0) correlated well with AUC(0-4) (r=0.

Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous and intermittent infusion in liver transplant patients.

Background: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous infusion might have pharmacodynamic advantages.

Objectives: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation.

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.

Objective: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure.

Summary Background Data: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL.

Recipient ctla-4 +49 G/G genotype is associated with reduced incidence of acute rejection after liver transplantation.

The aim of this pilot study was to investigate whether acute rejection after liver transplantation is associated with known single-nucleotide polymorphisms (SNPs) in the CD86- and CTLA-4 genes of liver-transplant donors and recipients. Single nucleotide polymorphisms were determined in 135 liver transplant recipients and in 73 donors. Acute rejection was not associated with CD86 + 1057 G/A genotype distributions in donors and in recipients.

Inflammatory bowel disease and liver transplantation for primary sclerosing cholangitis.

Objectives: To compare the outcome of liver transplantation in primary sclerosing cholangitis (PSC) patients with and without inflammatory bowel disease (IBD), and to analyse the influence of the transplantation on the course of IBD.

Methods: Retrospective analysis of the data regarding PSC, IBD, and liver transplantation in all patients transplanted for PSC.

Setting: Single university transplantation centre.

Successful liver transplantation in a patient with sickle-cell anaemia.

Liver transplantation in the setting of sickle-cell anaemia poses several new challenges to the transplant team. Hypoxaemia, acidosis and a decrease in body temperature are common occurrences that can cause sickling in the peri-operative period, putting the patient at risk of sickle-cell crises or graft dysfunction. We describe a patient with sickle-cell anaemia who successfully underwent transplantation, and we discuss the rationale of various precautions that had to be taken.

Blockade of intragraft IL-2 receptor-alpha by basiliximab is insufficient to prevent activation of liver graft infiltrating cells.

Treatment with basiliximab, a CD25 (Interleukin-2 receptor-alpha; IL-2Ralpha)-blocking human-murine chimeric antibody, reduces the incidence of acute rejections after organ transplantation, but rejection is not completely prevented. We investigated whether rejections during basiliximab treatment were due to insufficient exposure to the antibody or to incomplete blockade of intragraft CD25, and whether CD25-blockade affected activation of liver transplant infiltrating cells. Twenty-seven basiliximab-treated liver transplant recipients and seven patients not treated with basiliximab, from which post-transplant liver biopsies were available, were retrospectively selected for this study.

Mycophenolic acid is a potent inhibitor of the expression of tumour necrosis factor- and tumour necrosis factor-receptor superfamily costimulatory molecules.

The tumour necrosis factor (TNF) ligands CD154, CD70 and TNF receptors CD134 and CD137 are all involved in allograft rejection. Because these molecules are not present on resting T cells, we investigated whether immunosuppressive drugs could inhibit their induction. Expression was induced in vitro on T cells by phorbol 12-myristate 13-acetate and ionomycin or by allogeneic dendritic cells in the presence or absence of cyclosporin A (CsA), tacrolimus (TAC), rapamycin derivative (SDZ RAD), or mycophenolic acid (MPA), and determined by flow cytometry.

Expression of CD80 on Kupffer cells is enhanced in cadaveric liver transplants.

In experimental animals inhibition of T cell co-stimulation immediately after organ transplantation effectively prevents rejection. We investigated whether the expression of co-stimulatory molecules is enhanced in cadaveric liver transplants, whether their expression is influenced by the transplantation procedure, and whether variation in expression between liver transplants is related to the occurrence of acute rejection. Expression of CD80, CD86 and the macrophage marker CD68 were determined by immunohistochemistry in biopsies from 40 clinical liver transplants obtained at different time-points during the transplantation procedure, and in normal liver tissue obtained from 10 human livers.

Basiliximab interferes with the detection of soluble IL-2 receptor by the Immulite Immunoassay system.

The use of the Immulite Automated Immunoassay system is becoming an increasingly popular method for accurate and fast measurement of sIL-2R in serum. Here, we report that detection of sIL-2R using the Immulite Immunoassay system in serum samples of patients who are treated with basiliximab, a monoclonal antibody against the alpha-chain of the IL-2 receptor, may lead to false measurements.

Portal flow diversion is essential for graft survival in canine auxiliary partial orthotopic liver transplantation.

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intra-operative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband.

Are cytokine gene polymorphisms related to in vitro cytokine production profiles?

Currently, there is much interest in the genetic basis for diseases or disease manifestations and, in particular, in whether they are related to cytokine gene polymorphisms. It has become accepted to denote such single-nucleotide polymorphisms of cytokine genes by their presumed association with high or low in vitro cytokine production. In this article, we analyze the relationship between cytokine gene polymorphisms and in vitro tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), and interleukin (IL)-10 and IL-13 production, both in liver transplant recipients and in healthy volunteers.

Early differentiation between rejection and infection in liver transplant patients by serum and biliary cytokine patterns.

Background: Differentiation between acute liver graft rejection and infection remains a clinical challenge during the early posttransplantation period. Although cytokines play a pivotal role in mediating allograft rejection, previous studies demonstrate that most cytokines are not specific for liver graft rejection or infections. However, other studies suggest that adhesion molecules and cytokines in bile reflect the immunologic activity within the liver more closely.

Granzyme expression in fine-needle aspirates from liver allografts is increased during acute rejection.

We investigated whether determination in fine-needle aspiration biopsy (FNAB) specimens of cells expressing granzymes (Grs) and Fas ligand would provide a reliable, easy, and quantitative measure of rejection activity in the transplanted liver. Retrospectively, 13 FNAB specimens obtained during clinical acute rejection, 10 FNAB specimens obtained during subclinical rejection, 12 FNAB specimens obtained during cytomegalovirus (CMV) infection, and 26 FNAB specimens obtained in the absence of rejection or infection were included on the study. Cytospin preparations of FNAB and peripheral-blood specimens were immunocytochemically stained for Fas-ligand and Gr, and increments in the liver were calculated by subtracting frequencies of positive cells in blood from those in FNAB specimens.

[The pregnant patient with acute liver disease].

Acute liver disease was diagnosed in three pregnant patients: two 30-year-old women had a 'haemolysis, elevated liver enzymes, low platelets' (HELLP) syndrome and acute fatty liver of pregnancy, respectively, and a 20-year-old woman had acute liver failure due to acute hepatitis B. The first two patients had a caesarean section, the third one delivered her child, which died spontaneously shortly after birth at a gestational age of 23 weeks. She was then treated by liver transplantation.