Catherine Edwards-Smith

Serum levels of interleukin-10 (IL-10) are elevated in a proportion of patients with untreated chronic hepatitis C, and this may compromise the host immune response to the virus. The capacity for IL-10 production varies according to the genetic composition of the IL-10 locus. We examined the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with chronic hepatitis C and their association with response to treatment with interferon alfa (IFN-alpha). After adjusting for potential confounding variables, a highly significant relationship was found between inheritance of the IL-10 promoter -592*A and -819*T alleles or the ATA haplotype and response to IFN-alpha therapy (P =.016). Response to treatment was also associated with viral genotype 3a, a low viral load, and less fibrosis on liver biopsy. Following in vitro stimulation of peripheral blood mononuclear cells, the IL-10 promoter haplotypes, GCC, ACC, and ATA, were associated with high, intermediate, and low IL-10 production, respectively. These findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis C to IFN-alpha therapy. Patients who are genetically predisposed to high IL-10 production have a poor response to IFN-alpha and may benefit from additional treatment strategies designed to enhance a T-helper type 1 (Th1) response.

Progressive hepatic fibrosis and cirrhosis develops in 20% to 30% of patients with chronic hepatitis C virus (HCV). We propose that host genetic factors influencing fibrogenesis may account for some of the variability in progression of this disease. In progressive fibrosis of other organs, particularly heart and kidney, production of the profibrogenic cytokine, transforming growth factor beta1 (TGF-beta1), may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The inheritance of polymorphisms in TGF-beta1, interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and genes of the renin-angiotensin system was examined in 128 patients with chronic HCV. The influence of genotypes on the stage of hepatic fibrosis was tested after adjustment for potential confounders (age, gender, alcohol consumption, portal inflammation, and steatosis), which may have independent effects on histological severity. The stage of fibrosis was 0 in 30 (23.4%), 1 in 44 (34.4%), 2 in 27 (21.1%), and 3 or 4 in 27 (21.1%). A statistically significant relationship was seen between inheritance of high TGF-beta1- and angiotensinogen (AT)-producing genotypes and the development of progressive hepatic fibrosis. This association persisted after correcting for potential confounders. Patients who inherited neither of the profibrogenic genotypes had no or only minimal fibrosis. Knowledge of these polymorphisms may have prognostic significance in patients with chronic HCV and may direct more aggressive therapy towards those patients with an increased risk of disease progression. The documentation of a significant relationship between AT genotype and fibrosis raises the novel suggestion that angiotensin II may be another mediator of extracellular matrix production in the liver.

The tolerance induced by orthotopic liver transplantation (OLT) in certain combinations of rat strains can be prevented by total body irradiation (TBI) of the donor. We demonstrate here that the intravenous inoculation of splenic leukocytes into irradiated donors before OLT could re-establish tolerance in association with a state of microchimerism detected in the recipients. When donor DA (RT1a) strain rats were irradiated with 1000 rad 24 h before liver harvesting and subsequent liver implantation into PVG recipients, five out of six rats died from rejection in this normally tolerogenic OLT (DA-PVG) combination. Injection of 1.5 x 10(8) splenic leukocytes from naive DA rats into the irradiated DA donor rats 24 h before OLT restored the tolerogenic potential of the liver allografts. Immunofluorescence assay revealed an increased number of donor (DA) type cells in the PVG recipient bearing a repopulated DA liver, compared to the PVG recipient of an irradiated liver. These results suggest that passenger leukocytes reconstituted by splenic leukocytes have the capacity to protect liver allografts.

Abstract The tolerance induced by orthotopic liver transplantation (OLT) in certain combinations of rat strains can be prevented by total body irradiation (TBI) of the donor. We demonstrate here that the intravenous inoculation of splenic leukocytes into irradiated donors before OLT could re-establish tolerance in association with a state of microchi-merism detected in the recipients. When donor DA (RT1a) strain rats were irradiated with 1000 rad 24 h before liver harvesting and subsequent liver implantation into PVG recipients, five out of six rats died from rejection in this normally tolerogenic OLT (DA-PVG) combination. Injection of 1.5 times 108 splenic leukocytes from naive DA rats into the irradiated DA donor rats 24 h before OLT restored the tolerogenic potential of the liver allografts. Immunofluorescence assay revealed an increased number of donor (DA) type cells in the PVG recipient bearing a repopulated DA liver, compared to the PVG recipient of an irradiated liver. These results suggest that passenger leukocytes reconstituted by splenic leukocytes have the capacity to protect liver allografts.

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-beta, interleukin-10, and tumor necrosis factor alpha (TNF-alpha) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P =.001), immune-mediated liver disease (P =.018), normal pre-OLT creatinine clearance (P =.037), and fewer HLA class 1 mismatches (P =.038) were independently associated with rejection. Renal impairment occurred in 80% of patients and was moderate or severe in 39%. Clinical variables independently associated with renal impairment were female sex (P =.001), pre-OLT renal dysfunction (P =.0001), and a diagnosis of viral hepatitis (P =.0008). There was a significant difference in the frequency of TNF-alpha-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-alpha-308 polymorphism and graft rejection approached significance (P =.06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT. Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions.