creases in soluble immune factors, such as serum An imbalance between T helper cell (Th)1 and Th2-interleukin-2 (IL-2) receptor have provided peripheral evilike cytokines has been described in several chronic dence that significant intrahepatic anti-HCV immune proinfectious diseases. We therefore analyzed the intrahecesses may be occurring. 4 However, there is a paucity of patic messenger RNA (mRNA) expression of Th1-like (indata relating to the intrahepatic expression of cytokines that terleukin [IL]-2, interferon [IFN]-g) and Th2-like (IL-4, may be expected to mediate any immune response in the IL-10) cytokines in chronic hepatitis C patients (n Å 17) liver in chronic HCV infection. and controls (n Å 6) and correlated the results with liver Cytokines are regulatory molecules that play an important histology and intrahepatic viral load. Intrahepatic cytorole in many physiological and pathological processes. CD4/ kine mRNA and hepatitis C virus (HCV) RNA were quan-T cells, which are central to the induction of anti-viral retitatively assessed by polymerase chain reaction (PCR) sponses, have been subdivided according to two predominant using a dot-blot hybridization technique. Liver biopsy cytokine secretion profiles originally described in mouse Tspecimens were histologically graded using the Scheuer cell clones. 5 T helper (Th) 1 cells produce cytokines such as Score. IFN-g and IL-2 mRNA expression were signifi-IL-2 and interferon-g (IFN-g) which are important factors cantly upregulated in chronic HCV vs. controls (P õ .002, responsible for promoting the cell-mediated immune re-P õ .04, respectively). Both correlated significantly with sponse. In contrast Th2 cells produce cytokines such as IL-4 histological fibrosis and portal tract inflammation. In contrast, the expression of IL-10 mRNA was decreased and IL-10, which mediate the humoral response. However, in cirrhosis and chronic HCV compared with controls (P it is now recognized that these cytokines can be produced õ .02, P õ .0001, respectively). IL-4 mRNA was detected by cells other than CD4/ T cells and therefore it has been inconsistently at low levels in all groups. Intrahepatic suggested that these polarized cytokine responses be referred viral load did not correlate with either cytokine expres-to as Th1-like or type 1 and Th2-like or type 2 responses. 6 sion or tissue injury. In conclusion, the progressive liver Recently the relationship of Th1 versus Th2-like cytokines injury seen in chronic HCV is associated with the upreg-in chronic infections such as human immunodeficiency virus, ulation of intrahepatic Th1-like cytokines and the down-leprosy, and leishmaniasis has been explored.6-10 A decrease regulation of IL-10, a Th2-like cytokine. These results in cell-mediated immunity, i.e., a Th2-type profile, has been suggest a role for delayed-type hypersensitivity immune suggested to be associated with increased pathogen load and reactions in HCV related liver injury. (HEPATOLOGY progressive disease. It is unknown whether chronic HCV in-1996;24:759-765....

The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.

Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohn's disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohn's disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease.

Chronic hepatic regeneration constitutes an important part of the cirrhotic process. The factors regulating chronic hepatic regeneration, however, remain unclear. We therefore analyzed the intrahepatic messenger RNA (mRNA) expression of growth factors (epidermal growth factor [EGF], basic fibroblast growth factor [bFGF], hepatocyte growth factor [HGF], transforming growth factor [TGF]-alpha, and TGF-beta) at progressive time points (postoperative days 2, 7, 14, and 21) in a rat bile duct-ligated (BDL) model of cirrhosis versus sham controls. Intrahepatic growth factor mRNA expression was quantitatively assessed by polymerase chain reaction (PCR) using a dot-blot hybridization technique. Cirrhosis was associated with statistically significant (P < .05) progressive increases in the intrahepatic mRNA expression of bFGF (80-fold), EGF (25-fold), and TGF-beta (fourfold) in BDL animals versus controls. Furthermore, immunohistochemistry of hepatic sections showed a progressive up-regulation of bFGF protein in areas of bile duct proliferation. These areas also showed a dramatic increase in the number of hepatic stellate cells (HSC). In contrast, the intrahepatic expression of hepatocyte growth factor (HGF) mRNA was only significantly increased at postoperative days 7 and 14 in BDL animals before returning to control levels as cirrhosis developed. There were no significant differences found at any timepoint in the expression of TGF-alpha in BDL animals versus controls. In conclusion, the development of cirrhosis in this BDL rat model was associated with a progressive increase in the intrahepatic expression of EGF, bFGF, and TGF-beta. Early increased expression of HGF was not maintained in established cirrhosis. The findings suggest that these growth factors may play important roles in the pathogenesis of chronic hepatic regeneration in cirrhosis.