The prevalence of antibodies to hepatitis C virus (HCV) was investigated in 129 patients with chronic liver disease (85 with chronic active hepatitis and 44 with cirrhosis) and 53 patients with hepatocellular carcinoma. The commercially available second generation anti-HCV enzyme immunoassay kit was used. Antibodies to hepatitis C virus were detected in 16.2% of the patients with chronic liver disease and in 15.1% with hepatocellular carcinoma. Of the HCV positive patients in all groups 51.7% were positive for hepatitis B virus (HBV) markers indicating present or past infection. Prevalence of HBV markers in all the three groups (CAH, cirrhosis and HCC) was higher as compared with anti-HCV prevalence. These results suggest that HCV infection may not be a major cause of chronic liver disease and hepatocellular carcinoma in India and indicate the presence of other aetiological agents.

Adolescent↗

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Polymerase chain reaction.

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DNA Fingerprinting↗

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Chronic hepatitis in a large Indian hospital.

BACKGROUND: In developed countries as well as in Southeast Asia, the hepatitis B and C viruses are the main causes of chronic hepatitis. In India, however, there have been no major investigations on the aetiology of chronic hepatitis. (The hepatitis E virus which is responsible for half the sporadic and most of the epidemic cases of acute viral hepatitis in India does not cause chronic disease.) We, therefore, studied the profile of chronic hepatitis in India. METHODS: The clinical presentation, aetiology, serology and histological changes were studied prospectively in 48 patients with chronic hepatitis admitted to the All India Institute of Medical Sciences, New Delhi. Of these, 44 (92%) had chronic active hepatitis, 3 (6.3%) had chronic persistent hepatitis and 1 (2%) had chronic lobular hepatitis. RESULTS: The hepatitis B virus was the aetiological agent in 24 (50%) of these patients, the hepatitis D virus in association with hepatitis B virus in 10 (21%), the hepatitis C virus in 7 (15%) and the non-A, non-B viruses other than the hepatitis C virus in 6 (13%). One patient (2.0%) had autoimmune chronic active hepatitis. Jaundice at presentation was seen in 33 (69%) patients and more than half had hypoalbuminaemia (< 3 g/dl) with a prolonged prothrombin time. Alanine aminotransferase levels were less than 5 times above normal in over two-thirds of the patients. The highest alanine aminotransferase values were observed in patients with hepatitis D virus infection whereas the lowest were seen in patients with non-A, non-B related chronic active hepatitis. Histological examination revealed bridging necrosis in 40 (91%) patients with chronic active hepatitis indicating a severe form of disease. Replication of the hepatitis B virus was seen in 13 patients with chronic hepatitis, 5 of whom had hepatitis D virus-induced chronic hepatitis. Patients with hepatitis B virus replication had higher alanine aminotransferase values and more severe bridging necrosis than patients who did not have replicating viruses. Higher alanine aminotransferase values, ascites and oesophageal varices were encountered more frequently in patients with hepatitis B and D virus than in those with non-A, non-B related chronic hepatitis. CONCLUSION: Chronic hepatitis is not uncommon in India. It presents with evidence of severe disease and, as elsewhere, is most frequently caused by the hepatitis B virus.

Adult↗

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Expression of costimulatory molecules: B7 and ICAM up-regulation after treatment with a suicide gene.

The herpes simplex virus thymidine kinase gene (HSV-TK) in combination with ganciclovir (GCV), is currently being used in gene therapy-based clinical trials for cancer treatment. Its therapeutic effect is based on a "bystander effect" whereby HSV-TK gene-modified tumor cells are toxic to nearby unmodified tumor cells when exposed to the antiviral drug GCV. We have recently hypothesized that the in vivo mechanism of this bystander effect is due to alterations in the tumor microenvironment in response to release of cytokines and an infiltration of leukocytes after treatment with HSV-TK gene-modified tumor cells and GCV, which results in tumor regression. Expression of B7, a recently identified costimulatory molecule that is important for T-cell stimulation, has been shown to be modulated by stimulatory cytokines interferon-gamma, tumor necrosis factor-alpha, and inhibited by interleukin-10. In the present study, we investigated whether the cytokines released after HSV-TK and GCV treatment could include the expression of the costimulatory molecules B7-1 and B7-2 and the adhesion molecule (ICAM)-1 in the tumor. Furthermore, we investigated whether this altered environment affected the antitumor properties of host lymphocytes. An in vitro model was developed to establish the effects of HSV-TK gene-modified tumor cells and GCV on tumor infiltrating cells. The murine macrophage cell line (IC21) was exposed to either supernatants or cell lysates collected from a mixture of HSV-TK-transduced (KBALB-STK) and non-transduced (KBALB) murine fibrosarcoma tumor cells previously exposed to GCV (experimental). Immunohistochemical analysis showed a significant expression (P < .0001) of B7-1 and B7-2 post exposure of IC21 cells to either supernatant or lysate. In contrast, the level of expression in IC21 cells exposed to the control lysate or supernatant remained unchanged for B7-1 and B7-2. In vivo analysis for B7-1 and B7-2 expression by immunohistochemistry in tumor tissues from experimental mice receiving HSV-TK gene-modified tumor cells and GCV treatment showed a significant expression of B7.1 (35%, P < .0001) and B7.2 (38.2%, P < .0001) on tumor-infiltrating mononuclear cells. In contrast, tumor-bearing control animals showed low levels of B7-2 expression (5.8%), whereas B7-1 was undetectable, as confirmed by reverse-transcriptase polymerase chain reaction. In addition, a significant up-regulation of ICAM expression (50%) on tumor tissues was observed in the experimental group (P = .0317) as compared with the control group (25%). Furthermore, T cells isolated from experimental mice showed a significant in vitro proliferative response (p = .0202) when exposed to syngeneic tumor cells as compared with the control group. These data demonstrated that the use of HSV-TK gene-modified tumor cells and GCV as a suicide gene in the treatment of an intraperitoneal tumor resulted in the expression of the B7 costimulatory molecules and ICAM-1 adhesion molecule and enhanced proliferative response of host T cells. These findings help to understand the mechanism of tumor cell killing in vivo using HSV-TK gene-modified tumor cells.

Animals↗