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We report our single center experience with the use of basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), in combination with a steroid- and tacrolimus-based regimen in adult to adult living-related liver transplantation (ALRLT). Sixty consecutive ALRLTs were analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels) and a dose regimen of steroids (starting with 20 mg iv, switched to po as soon as the patient was able to eat, and weaned off within 1-2 months). Follow-up ranged from 6 to 1699.4 days after transplantation (mean 517.5 days, SD +/- 413.4; median 424 days). Of the recipients, 95% remained rejection-free during follow-up, with an actuarial rejection-free probability of 96.61% within 3 months. Three patients had episodes of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graft survival rates at 3 years were 82.09% and 75.61%. Six patients (10%) experienced sepsis. There was no evidence of cytomegalovirus infections or side-effects related to the basiliximab. We found zero de novo malignancy, although we observed 5 patients with metastatic spread of their primary malignancy during the follow-up. Basiliximab in association with tacrolimus and steroids is effective in reducing episodes of ACR and increasing ACR-free survival after ALRLT.

Arteroportal fistula is a rare cause of prehepatic portal hypertension. A 44-year-old male with hepatitis virus C infection was admitted for acute variceal bleeding. Endoscopy showed the presence of large esophageal varices. The ultrasound revealed a mass near the head of pancreas, which was characterized at the color-Doppler by a turbulent flow, and arterialization of portal vein flow. CT scan of abdomen showed a large aneurysm of the gastroduodenal artery communicating into the superior mesenteric vein. The sinusoidal portal pressure measured as hepatic vein pressure gradient was normal, confirming the pre-hepatic origin of portal hypertension. The diagnosis of extrahepatic portal hypertension secondary to arteroportal fistula was established, and the percutaneous embolization was performed. Three months later, the endoscopy showed absence of esophageal varices and ascites. At the moment, the patient is in good clinical condition, without signs of portal hypertension.

The proportion of chronic liver disease associated with the pre-core mutant of hepatitis B virus (HBV) infection is increasing, particularly in Mediterranean Europe and in Asia. The pre-core mutant HBV is unable to produce hepatitis B e antigen (HBeAg), so that patients with this variant do not present with HBV characterised by HBeAg in the serum. Pre-core mutant chronic hepatitis B infection usually proceeds to serious liver disease. Wild-type HBV infection may be mild and respond relatively well to interferon (IFN) alpha therapy, but IFN alpha is not an effective therapeutic option in pre-core mutant hepatitis B infection and new therapeutic options are needed. Clinical data show that lamivudine is an effective treatment for patients with pre-core mutant hepatitis B. There is profound suppression of HBV replication and improvement in indicators of liver disease in most patients. In conclusion, lamivudine is suitable for treatment of a wide range of patients with chronic hepatitis B, including those with pre-core mutant HBV infection., (Copyright 2000 Wiley-Liss, Inc.)

Hepatocellular carcinoma (HCC) is closely associated with cirrhosis, but it also develops, although much less frequently, in a non-cirrhotic liver. It is suspected that hepatocellular carcinoma has a different etiology when associated and not associated with chronic liver disease. We report two cases of patients with hepatocellular carcinoma that developed in a non-cirrhotic liver. In the first case we describe an incidental liver nodular lesion containing multiple foci of HCC including pseudogland or trabecular formation and areas of sclerosis. The non-cancerous parenchyma of the liver was histologically unremarkable except for mild fatty changes of hepatocytes and minimal dysplasia. The second case describes a combined hepatocellular carcinoma and cholangiocellular carcinoma (CCC) (mixed carcinoma) in a patient who was serologically negative for both hepatitis B and C viruses. The adjacent liver parenchyma showed mild piecemeal necrosis and mild lobular activity compatible with chronic viral hepatitis, but cirrhosis was not established. This case appears to indicate that mixed type carcinoma can develop in a non-cirrhotic liver, with CCC being far more dominant than HCC; such a finding is extremely unusual, based on previously published reports.

This placebo controlled, double-blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n = 60) or placebo for 26 weeks (n = 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P <.001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine-treated patients. At week 52, 60% of lamivudine-treated patients with liver biopsy specimens available showed histological improvement (>/=2-point reduction in Knodell necro-inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post-treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg-negative patients is similar to the response reported in previous studies of patients with HBeAg-positive chronic hepatitis B.

Background: Four every ten patients receiving high-dose parenteral steroids for severe ulcerative colitis fail and may have their colon removed. Intravenous followed by oral cyclosporin has been shown to initially rescue approx. 70% of these non-responder patients, but dosages and long term-efficacy are still debated. We reviewed the clinical outcomes of patients treated with cyclosporin for refractory ulcerative colitis at our Center in the last 7 years., Methods: Fifty-four patients destined to colectomy because of refractory ulcerative colitis (previous failure to respond to 7 days of 1 mg/kg/day steroids) were enrolled to initially receive a two-week continuous infusion of 2 mg/kg/day cyclosporin. Responders (showing at least a 50% reduction of activity) were meant to be treated with oral drug at 6-8 mg/kg/day for 6 months with the maintenance of remission and the spare of steroids being the end-points., Results: Data are available for 47 patients followed-up for a minimum of 6 months up to 6 years. Of these 47, 14 did not respond to the intravenous drug and were submitted to surgery; of the remaining 33 responders (70%) entering the oral 6-month phase, 17 relapsed before end or on leaving the drug and were considered as failures. The remaining 16 (34% of the 47) left cyclosporin in remission and in need of less than 20 mg steroids daily. Of them, 12 avoided colectomy in a follow-up of 6 months-6 years., Conclusions: Intravenous cyclosporin may be rapidly effective in 7 every 10 patients whose acute ulcerative colitis fails a full-dose steroid course. However, only 3 of the initial 10 may maintain remission over a 6-month oral course. Further efforts should concentrate on improving the long term efficacy of cyclosporin.

We assessed the pattern of hepatitis C viremia in chronic liver disease by studying 100 hepatitis C virus antibody-positive patients: 48 with chronic hepatitis, 21 with cirrhosis and 31 with hepatocellular carcinoma and cirrhosis. Serum hepatitis C virus RNA was detected by means of both the conventional nested polymerase chain reaction and a newly developed assay based on branched DNA that can also quantify viremia. Hepatitis C virus RNA was found in 94 of 100 patients with polymerase chain reaction and in 71 of 100 patients with branched-DNA (p < 0.001). Mean viremia level (x 10(3) genome equivalents/ml +/- S.D.), as assessed with the branched-DNA test, was 5,700 +/- 7,618 in the 48 patients with chronic hepatitis, 3,340 +/- 3,633 in the 21 patients with cirrhosis and 1,768 +/- 2,770 in the 31 patients with hepatocellular carcinoma (p < 0.02). We also analyzed retrospectively the relationship between viremia and treatment. Fifty-five patients (41 chronic hepatitis, 14 cirrhosis) underwent interferon-alpha treatment. Mean viremia level was comparable among the 30 responders (5,644 +/- 8,207) and the 25 nonresponders (5,519 +/- 6,208) to interferon, but it was significantly lower (1,841 +/- 1,864) in the 12 of 30 responders (11 chronic hepatitis, 1 cirrhosis) who maintained remission up to 1 yr after cessation of interferon treatment. Fourteen patients (7 chronic hepatitis, 7 cirrhosis) with autoantibodies (12 antinuclear, 2 anti-liver-kidney microsomal) were treated with prednisone. The mean viremia level significantly increased after 3 mo of treatment, even in face of ALT decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

This study analyzed new cell lineage markers for the differential diagnosis between hepatocellular carcinoma (HCC) and cholangiocarcinoma (ChC), as well as the potential pathways of cell-cell and cell-extracellular matrix interactions of neoplastic liver cells during tumor spread and invasion, by comparing the expression of (VLA) integrins, vitronectin receptor, and neural cell adhesion molecule in normal, inflamed, and neoplastic human liver biopsies. All cases of liver cell adenoma and well-differentiated HCC expressed the same set of integrins as observed in normal liver tissue, i.e., VLA-alpha 1 and VLA-beta 1. Poorly differentiated HCC also expressed VLA-alpha 1 and VLA-beta 1, but in addition de-novo expressed VLA-alpha 2, VLA-alpha 3, VLA-alpha 6 and vitronectin receptor. All cases of well-differentiated ChC expressed an identical integrin immunoprofile as observed in normal bile duct epithelium, i.e., VLA-alpha 2, VLA-alpha 3, VLA-alpha 6, VLA-beta 4 and vitronectin receptor, whereas poorly differentiated ChC showed a markedly decreased expression of these integrin subunits. VLA-alpha 1 was constantly absent from all cases of ChC, whereas VLA-beta 4 was never expressed by HCC. Neural cell adhesion molecule, exclusively expressed by proliferating reactive bile ductules in cholestatic and regenerating liver, was constantly absent from both malignant neoplasms. In conclusion, the integrin make up of various liver tumors closely follows that of their normal counterparts. Differences in integrin receptor expression vary according to the cellular origin of the tumors and are associated with a poor differentiation. Our findings suggest that immunohistochemical staining for VLA-alpha 1 and VLA-beta 4 integrin subunits, which highlight the cellular phenotype of the two neoplasms, might be a helpful tool in the differential diagnosis between HCC and ChC.

During the last few years, there has been a growing evidence that hepatocytes are not merely 'passive' target cells for immunological attack by effector T-cells, but may play a more 'active' role in the initiation and perpetuation of the immune response. Immune modulators released by inflammatory cells at the site of inflammation, as well as the eliciting antigen itself, are able to modulate the phenotype of hepatocytes. This would result in abnormal cytokine production and/or cytokine/receptor expression, as well as active synthesis and display of surface immune 'activation' markers and adhesion molecules, which act as co-stimulatory signals for T-cell activation. These accessory functions involve multiple molecular pathways of cell-cell interactions, which in turn will enable hepatocytes to play a role as 'accessory' cells in both the afferent and efferent arms of the cell-mediated immune response.

The expression of the selectin receptor LAM-1/Leu 8 was analysed in normal and in inflamed liver tissue, and its expression on mononuclear inflammatory cells was correlated with their topographical distribution in various compartments of the inflamed liver, in order to obtain new insights on possible molecular mechanisms involved in the traffic of mononuclear inflammatory cells throughout the diseased hepatic parenchyma. In normal liver tissue, few scattered mononuclear cells in portal and lobular parenchyma corresponded to both CD4+ and CD8+, as well as to CD45RA+ (2H4+) naive and CD45RO+ (UCHL1+) memory T cells, and were LAM-1/Leu 8+. In acute and chronic inflamed liver biopsies, CD45RO+ (UCHL1+) CD4+ and CD8+ memory T cells largely predominated in both portal and lobular parenchyma. The expression of LAM-1/Leu 8 antigen on these memory T cells varied according to their localization in the liver parenchyma, and it was not correlated with specific aetiological causes. In acute hepatitis, the vast majority of T lymphocytes were LAM-1/Leu 8-. In chronic active hepatitis, memory T cells in portal tracts expressed LAM-1/Leu 8, whereas virtually all intralobular T cells accumulating in areas of periportal and intralobular inflammation were LAM-1/Leu 8-. In chronic persistent hepatitis, the LAM-1/Leu 8+ T cells largely predominated among the numerous mononuclear inflammatory cells within enlarged portal tracts, whereas LAM-1/Leu 8- T cells were restricted to areas of intralobular 'spotty' inflammation. Therefore, two phenotypical populations can be recognized among the memory T cells in inflamed liver tissue, according to their topographical localization: LAM-1/Leu 8+ T cells predominating in portal tracts, and LAM-1/Leu 8- T cells predominating in the lobular parenchyma. These data show that during their migration through the inflamed liver parenchyma, memory T lymphocytes undergo phenotypical changes (LAM-1/Leu 8 shedding) according to their localization in different liver compartments (portal tracts vs. lobular parenchyma), suggesting multiple cellular and molecular mechanisms involved in the regulation of the leucocyte traffic through inflamed liver tissue.

We have examined the in-situ distribution of type A and type B receptors for tumor necrosis factor (TNF) in normal and diseased human liver biopsy specimens. In normal liver tissue, no or very small amounts of TNF receptors were found. In acute and chronic inflammatory liver diseases, a strong up-regulation of the expression of both TNF receptors was found on hepatocytes, bile duct epithelium, sinusoidal lining cells and mononuclear inflammatory cells. With immunoelectronmicroscopy, all these cells showed cytoplasmic, in addition to membranous staining, suggesting active synthesis of the receptor or, alternatively, internalization of the receptor and its ligand. This up-regulated expression of both type A and type B receptors for TNF was similar in acute and chronic active hepatitis, and was not related to the etiology of the liver disease, nor restricted to areas of liver inflammation. Our results indicate that hepatocytes, sinusoidal endothelial cells, bile duct epithelial cells and mononuclear inflammatory cells, by displaying receptors for TNFs, represent target cells for both these cytokines. Up-regulated expression of type A and type B receptors for TNFs endows these cells with augmented responsiveness for the pleiomorphic biological activities of these cytokines during liver injury.

Adhesion to and penetration through the sinusoidal vascular endothelium is a mandatory step for leukocyte migration and accumulation at sites of liver inflammation. This leukocyte trafficking is controlled by interactions between adhesion molecules on leukocytes and corresponding ligands on endothelial cells. We have analyzed the in situ distribution of two recently described vascular adhesion molecules (i.e., endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1) and of the lymphocyte "homing" receptor cluster of differentiation antigen-44 in normal and inflamed liver biopsy specimens. Endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 were absent from normal liver tissue, but they were strongly expressed on sinusoidal lining cells in inflammatory liver disease. Endothelial leukocyte adhesion molecule-1 expression predominated diffusely throughout the liver parenchyma in acute hepatitis; in contrast, vascular cell adhesion molecule-1 was mainly expressed in areas of periportal and intralobular inflammation in chronic active and persistent hepatitis. The "homing" receptor cluster of differentiation antigen-44 was weakly expressed on scattered mononuclear cells and on sinusoidal lining cells in normal liver tissue, but it was strongly up-regulated on mononuclear inflammatory cells and sinusoidal lining cells in acute and chronic hepatitis. In addition, reactivity for the cluster of differentiation antigen-44 was found on the membranes of variously sized clusters of hepatocytes in biopsy specimens with acute hepatitis. De novo or up-regulated expression of these adhesion molecules on sinusoidal lining cells in inflamed liver biopsy specimens indicates that these cells actively modulate their phenotype in response to environmental factors, thus playing a key role in the recruitment of leukocytes in acute and chronic liver inflammation.

The "very late activation" (VLA) subgroup of the integrin superfamily of adhesion molecules plays a central role in cell-cell and cell-matrix interactions. The six different VLA dimers known so far consist of a common beta subunit and a variable alpha (1 to 6) subunit. They serve as receptors for laminin, collagen, and fibronectin or function as adhesion molecules for leukocytes and are therefore of great significance in embryogenesis, growth and repair, and in leukocyte recirculation. The distribution of the common beta and the variable alpha chains of the VLA were studied in normal, inflammatory, and cholestatic liver biopsy samples. In normal liver tissue, vascular endothelia express alpha 1, 2, 3, 5, and 6; bile duct epithelium alpha 2, 3, 5, and 6; connective tissue stroma alpha 1 and 2; hepatocytes alpha 1 and 5; sinusoidal lining cells alpha 1, 2, and 5; and mononuclear cells alpha 4. Whereas bile ducts and vascular endothelia do not show relevant changes in alpha chain expression in liver diseases, hepatocytes de novo express membranous alpha 3 and 6 in inflammatory liver diseases. In view of the role of the VLA-3 and VLA-6 as laminin receptors, this finding is in line with the production of laminin in active liver disease. Moreover, de novo expression of "bile duct type" alpha 2, 3, and 6 on periportal hepatocytes in cholestatic liver disease likely illustrates a phenotypic switch of hepatocytes towards bile duct epithelium during cholestasis.

There is growing evidence that cellular adhesion mechanisms characterized by cell-cell and cell-matrix interactions are a fundamental process in the immunobiology of the cornea. Interactions with various extracellular matrix components are mediated by the very late activation (VLA) subgroup of the integrin superfamily of adhesion molecules. The six different VLA dimers known thus far consist of a common beta 1 subunit and a variable alpha (1 to 6) subunit. They serve as receptors for laminin (alpha 3 and alpha 6), collagen (alpha 2 and alpha 3), and fibronectin (alpha 4 and alpha 5). Using in situ immunohistochemistry and monoclonal antibodies, the distribution of the common beta 1 and the variable alpha-chains of VLA molecules was studied in normal human cornea and in cases with scarring or subepithelial/retrocorneal fibrous tissue. Epithelial cells were VLA-beta 1 and VLA-alpha 2, -alpha 3, -alpha 4, -alpha 5, and -alpha 6 positive. This is consistent with their intercellular adhesion and may aid in their attachment to the basement membrane which is composed of collagen, laminin, and fibronectin. Keratocytes in normal stroma expressed only the common beta 1-chain and no detectable alpha-chains. In regions of scar or fibrous tissue, however, an upregulated expression of the alpha-chains was detected. The VLA- alpha 1, -alpha 3, -alpha 4, and -alpha 5 were expressed in young fibrous tissue; in older lesions, VLA- alpha 1, -alpha 2, -alpha 3, -alpha 4, and -alpha 5 could be detected. The corneal endothelium showed a strikingly strong positivity for all VLA integrins.(ABSTRACT TRUNCATED AT 250 WORDS)

T cells can be divided into two main phenotypic subpopulations-i.e., the CD45RA-positive (2H4-positive) "naive" subset and the CD45RO-positive (UCHL1-positive) "memory" subset. In light of this recent functional reinterpretation of T-lymphocyte subpopulations, we reinvestigated the composition of the inflammatory infiltrate in liver biopsy specimens from patients with acute and chronic hepatitis. In normal liver, the few scattered mononuclear cells present in portal tracts and in the intralobular parenchyma consisted of both CD45RA-positive (2H4-positive) naive and CD45RO-positive (UCHL1-positive) memory T cells. In inflammatory liver diseases, portal tract and periportal and intralobular areas of inflammation consisted virtually only of CD45RO-positive (UCHL1-positive) memory T cells, which strongly expressed the CDw29 (4B4) antigen, and the adhesion molecules LFA-1, CD2, LFA-3, CD44 and VLA-4 and the activation marker human leukocyte antigen-DR. These results indicate that activated memory T cells represent the predominant subpopulation of lymphocytes in areas of liver inflammation. Memory T cells strongly express various homing receptors and adhesion molecules, which probably allow them to accumulate at inflammatory sites and to strengthen interaction with target cells. Furthermore, the increased number of memory T cells with enhanced interferon-gamma production in areas of liver inflammation may contribute to the maintenance and up-regulation of immune responses occurring in inflammatory liver diseases.

Using in situ immunohistochemistry and a specific monoclonal antibody (mcab R1G10), we analyzed the expression of the human interferon-gamma receptor (HuIFN-gamma R) and its topographical distribution in normal liver biopsies and in biopsies with various inflammatory liver diseases. In normal liver tissue, mcab R1G10 reacted weakly with sinusoidal and vascular endothelial cells, while hepatocytes were distinctly negative. In pathological conditions, mcab R1G10 produced membranous, cytoplasmic and/or perinuclear staining of hepatocytes, in a topographical distribution which varied according to the type of liver disease. In acute hepatitis, R1G10-positive hepatocytes were diffusely distributed throughout the liver parenchyma, and showed strong cytoplasmic, as well as membranous and perinuclear reactivity. In chronic persistent hepatitis, weak membranous staining was found on a number of scattered hepatocytes in acinar zone 1, with more pronounced expression on single hepatocytes in acinar zone 3. In chronic active hepatitis and in active cirrhosis, a diffuse weak membranous reactivity throughout the liver parenchyma was accompanied by enhanced R1G10 expression in areas of inflammation in acinar zone 1. With immunoelectronmicroscopy, R1G10 reactivity was found on the peripheral cell membrane and on the microvillous canalicular cell membrane of hepatocytes in a strikingly discontinuous manner. In the cytoplasm, the reaction product was detected on the cisternae of the rough endoplasmic reticulum and on small vesicles which were especially abundant in the perinuclear area. Our results demonstrate the absence of HuIFN-gamma R on hepatocytes in the normal liver, and its de novo expression during inflammatory liver disease. These findings indicate that hepatocytes, by displaying the HuIFN-gamma R, may act as target cells for the immunoregulatory action of IFN-gamma during liver inflammation.

In comparison to other cells involved in the hepatic immune response, dendritic cells in human liver tissue have received remarkably little attention. In view of their presence in normal liver, and their multiple immunological functions, it can be anticipated that dendritic cells are involved in viral, autoimmune and rejection immune responses of the human liver.

Cell-mediated immune reactions occurring in liver diseases involve infiltration of inflammatory cells into the hepatic parenchyma. Almost nothing is known about cellular and molecular mechanisms regulating this leukocyte traffic during the afferent and efferent arms of the hepatic immune response. This overview emphasizes that various liver parenchymal cells appear to participate actively in the development of the inflammatory response.

The in situ distribution patterns of intercellular adhesion molecule-1 and human leukocyte antigen-DR antigens were studied in serial sections of 61 liver biopsy specimens from patients with hepatitis B virus infection using immunohistochemical techniques. In addition, the topographical relationship between the display of HBcAg on one hand and the expression of intercellular adhesion molecule-1 by hepatocytes on the other was analyzed with a double-staining immunohistochemical procedure in 14 selected liver biopsy samples showing chronic persistent or chronic active hepatitis and signs of active hepatitis B virus replication as reflected by the presence of variable amounts of HBcAg in a nuclear or cytoplasmic pattern of immunoreactivity. Coexpression of intercellular adhesion molecule-1 and human leukocyte antigen-DR antigens by hepatocytes correlated positively with the site and extent of the inflammatory infiltrate, which was composed of lymphocytes expressing lymphocyte function-associated antigen-1. In healthy HBsAg-positive carriers without inflammatory liver disease, no intercellular adhesion molecule-1 or human leukocyte antigen-DR expression was found on hepatocytes; in acute hepatitis, intercellular adhesion molecule-1 and human leukocyte antigen-DR were strongly expressed throughout the liver parenchyma on liver cell membranes and on sinusoidal lining cells. In chronic persistent and chronic active hepatitis and in active cirrhosis, intercellular adhesion molecule-1 and human leukocyte antigen-DR showed membranous positivity on focal clusters of hepatocytes in areas of periportal or intraacinar inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Using monoclonal antibodies and in situ immunohistochemistry, we studied the distribution of "accessory" adhesion molecules (i.e., intercellular adhesion molecule-1 and leukocyte function-associated antigen-3) in 114 liver biopsy specimens with various inflammatory liver diseases and in 12 control liver biopsy samples without inflammation. The distribution of these adhesion molecules was compared with the presence on inflammatory cells of their natural ligands, lymphocyte function-associated antigen-1 and cluster of differentiation antigen-2, respectively. In normal liver, intercellular adhesion molecule-1 and leukocyte function-associated antigen-3 reacted weakly with sinusoidal lining cells, portal vessel endothelium and scattered mononuclear inflammatory cells, whereas hepatocytes were constantly negative. In contrast, all 114 biopsy samples of acute or chronic liver diseases revealed strong expression of intercellular adhesion molecule-1 and leukocyte function-associated antigen-3 on sinusoidal lining cells and on hepatocytes in areas of inflammation. Hepatocellular membrane positivity resulted in a "honeycomb pattern" of staining , which was panacinar in acute hepatitis and focal in chronic persistent or aggressive hepatitis. In various other chronic liver diseases, a multifocal periportal and intraacinar honeycomb pattern was detected. In all cases, a close topographical correlation was found between hepatocellular expression of intercellular adhesion molecule-1 and leukocyte function-associated antigen-3 on one hand and the presence of inflammatory cells expressing lymphocyte function-associated antigen-1 and cluster of differentiation antigen-2 on the other.(ABSTRACT TRUNCATED AT 250 WORDS)

The distribution of the thrombospondin-receptor was studied in 26 cases of inflammatory hepatitis B virus (HBV) related liver disease and twelve non-inflammatory controls using monoclonal antibody (mcab) OKM5. OKM5 reacted in all cases with sinusoidal lining cells, portal vessel endothelium, and scattered mononuclear inflammatory cells. In 16 of the 26 cases with inflammation, one or more clusters of OKM5 positive (OKM5+) hepatocytes were found in areas of periportal or intralobular inflammation, whereas the remaining ten cases did not show hepatocellular OKM5 reactivity. In all but one case, OKM5+ liver cells coexpressed HLA-DR-antigens, and in twelve cases cytotoxic/suppressor T-cells were enriched in the OKM5+/HLA-DR+ liver cell clusters, suggesting induction of OKM5 positivity by lymphokines released by nearby T-cells. In view of its role in cytoadherence, it is suggested that OKM5 expression by hepatocytes serves in the entrapment and retention of inflammatory cells thereby facilitating their activation. Furthermore, OKM5+/HLA-DR+ hepatocytes might trigger an autologous mixed lymphocyte reaction (AMLR), resulting in down-modulation of ongoing hepatic inflammatory responses.

Thirty-five patients with chronic viral hepatitis (B, D or non A, non B), treated with alpha interferon were evaluated by a highly sensitive enzyme immunoassay for the presence of alpha interferon neutralizing antibodies before and after three months of treatment. Although 4 subjects (11.4%) became immunized against alpha interferon, treatment with the drug was successful in inhibiting viral replication in 3 of them. We conclude that the appearance of anti alpha interferon antibodies does not affect the effectiveness of the drug, and is therefore not worth monitoring.