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Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, but tumor regression only rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions between monocytes/macrophages and T-cells/natural killer-cells, and in particular the role of such interactions for the outcome of cancer immunotherapy with interleukin-2. We propose that interleukin-2 therapy should be supplemented with compounds that alleviate toxicity inflicted by monocyte/macrophagederived reactive oxygen metabolites within and around tumors. The hypothesis is founded on data demonstrating that (i) functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen metabolites, generated by neighboring monocytes/macrophages, (ii) interleukin-2 only weakly activates T-cells or natural killer cells in an environment of oxidative stress, and (iii) inhibitors of the formation of reactive oxygen metabolites or scavengers of reactive oxygen metabolites, synergize with interleukin-2 to activate these lymphocyte subsets. We also review the preclinical background to the use of histamine dihydrochloride, an inhibitor of reactive oxygen metabolite formation in monocytes/macrophages, as a supplement to cancer immunotherapy with interleukin-2.

Summary Sixty-two anti-HCV and HCV-RNA positive Swedish blood donors (44 men, 18 women; median age 34 years) were studied. HCV genotypes were correlated to parenteral risk factors, liver morphology, serum alanine aminotransferase (ALAT) levels and HCV antibody profile. Forty percent of the donors were infected with HCV genotype 1a, 10% with 1b, 21% with 2b, and 29% with 3a. Intravenous drug use (IVDU) was more common in donors with genotype 3a than in those with genotype 1a (p=0.024), and prior blood transfusion more common in genotype 2b than in 3a (p=0.012). Chronic active hepatitis with and without cirrhosis was found in 38% of donors infected with genotype 2b as compared to 8% of donors infected with 1a (p=0.034). Forty percent of donors with genotype 1a had normal ALAT at the time of liver biopsy versus 11% with genotype 3a (p=0.046). Antibodies to C33c and C22-3 were present in nearly all donors whereas reactivity to C100-3 and 5-1-1 was detected more often in donors with genotypes 1a and 1b as compared to donors with genotypes 2b and 3a. In conclusion, genotype 3a was correlated to IVDU or tattooing as parenteral risk factors for the acquisition of HCV infection, and genotype 2b to prior blood transfusion. Donors with genotypes 1a seemed to have less severe liver disease than those infected with genotypes 2b and 3a.

Summary To achieve a more rapid antibody response following hepatitis B (HB) vaccination, vaccine injections were given to medical students at considerably shorter intervals than usually recommended. They received 10 µg of the Merck Sharp & Dohme recombinant HB vaccine at time 0, 2 and 6 weeks (27 vaccinees) or were vaccinated according to the recommended schedule for pre-exposure HB prophylaxis (0, 1 and 6 months) (26 vaccinees). The short interval regimen resulted in a significantly higher frequency of protective antibody levels (=10 IU/l) two weeks after the second dose of vaccine (48% vs. 4%; p<0.001), and all short interval vaccinees had seroconverted within two months (i. e. two weeks after the third dose). The recommended interval regimen resulted in a slower development of antibodies but significantly higher peak antibody levels after the completed three doses (p<0.001). The results indicate that protective antibody levels against hepatitis B virus (HBV) can be achieved more rapidly in humans through vaccination with short intervals. This short interval vaccination regimen, which has proved effective for post-exposure prophylaxis in chimpanzees, should possibly also be considered for post-exposure prophylaxis in humans, for instance after accidental exposure to HBV-contaminated blood.

Depletion of natural killer (NK) cells in vivo with anti-NK1.1 monoclonal antibody or anti-asialo-GM1 antiserum drastically reduced survival time in Swiss albino mice infected intravenously (i.v.) with herpes simplex virus type 2 (HSV-2). In contrast, depletion of NK cells did not affect the survival time of mice inoculated with HSV-2 by the intraperitoneal route. A single dose of histamine prolonged survival time in animals inoculated with HSV-2 i.v. but not in animals infected intraperitoneally. Treatment with the histamine H2 receptor antagonist ranitidine alone reduced survival time in i.v.-infected animals and blocked the protective effect of histamine. Histamine or ranitidine did not affect survival time in anti-NK1.1- or anti-asialo-GM1-treated animals. Our data suggest a role for histaminergic mechanisms in NK cell-mediated protection against HSV-2.

Background: The etiologic role of hepatitis B (HBV) and C virus (HCV) for hepatocellular carcinoma (HCC) in a low-endemicity area is obscure. Methods: Patients suspected of having primary liver cancer (PLC) in Göteborg, Sweden (n = 113), were tested serologically for HBV surface antigen and antibodies to HBV surface and core antigens. The presence of HBV surface and core antigens in cancer and non-neoplastic liver tissue in HCC cases was investigated immunohistochemically. Antibodies to HCV were tested by third-generation tests. The prevalence of HBV and HCV infection was compared in 73 patients with HCC and 32 patients with a final diagnosis other than PLC. Results: No patient had signs of chronic HBV infection. Seven of 64 (11%) HCC patients were anti-HCV-positive, compared with 1 of 31 (3%) without PLC. All seven patients with HCC and HCV infection had liver cirrhosis, and two were alcoholics. Alcoholism was judged the commonest (42%) cause of cirrhosis. Conclusion: Contrary to areas with a high incidence of HCC, chronic viral hepatitis, particularly HBV, seems to play a minor etiologic role for HCC in Sweden compared with alcohol-related cirrhosis.

A novel strategy for enhancing the efficacy of immunotherapy with interleukin-2 (IL-2) and interferon-α (IFN-α) in human neoplasia is presented. IL-2 and IFN-α are potent activators of the antitumour activity of natural killer (NK) cells but only rarely reduce the tumour burden in treated patients. Recent studies suggest that a reason why these cytokines are insufficiently effective in human cancer is that phagocytes inhibit the tumour-killing activity of NK cells at the site of the tumour. Histamine prevents the phagocyte-induced, NK cell-inhibiting signal; thus, histamine and IL-2 or histamine and IFN-α synergize to induce NK cell-mediated killing of human tumour cells in vitro. Further, treatment of tumour-bearing mice with histamine enhances IL-2- and IFN-α-induced destruction of NK cell-sensitive tumour cells in vivo.More than 50 patients with neoplastic disease have been treated with histamine, given in subcutaneous injections, together with IL-2 or IFN-α. The results of two pilot trials in metastatic melanoma suggest that the addition of histamine to IL-2 and IFN-α prolongs survival time and induces regression of tumours, such as liver melanoma, which are otherwise considered refractory to immunotherapy. The results of a trial in acute myelogenous leukaemia (AML) suggest that histamine and IL-2 protects AML patients against relapse of leukaemic disease. Histamine is well tolerated: for example, AML patients in remission have treated themselves with histamine at home without supervision for a total of >300 weeks with only a handful of therapy-related hospital contacts. Controlled trials in melanoma and AML are under way to further investigate the putative benefit of histamine in neoplastic disease.

HBeAg and anti-HBe were determined by radioimmunoassay (Abbott HBe.) in serial serum samples from 22 patients who had been HBsAg-positive for more than 1 year. Seventeen patients (77) were HBeAg-positive at onset of illness. Eight of these patients were persistently HBeAg-positive during 2.5–8.5 years' follow-up study (mean, 5.4 years). Chronic persistent hepatitis (CPH) developed in one of these patients and chronic active hepatitis (CAH) in seven patients. Nine persistently HBsAg-positive patients were transiently HBeAg-positive. Seven of these patients developed CPH, and they all lost HBeAg within 2 years of onset of illness. One patient, who was HBeAg-positive for 4 years, developed CAH with cirrhosis after loss of HBeAg. In five patients, HBeAg could not be detected. They were anti-HBe-positive at onset of illness; four developed CAH and/or cirrhosis, and one developed CPH. Progression from CPH or nonspecific reactive hepatitis to CAH was observed in two persistently HBeAg-positive patients. Prolonged detection of HBeAg in CPH is a reason for repeated liver biopsy to reevaluate the diagnosis. The behaviour of the e-antigen system in CAH seems to be more complex than in CPH, perhaps indicating a different pathogenetic mechanism of chronicity in CAH.

The occurrence of the delta (δ) agent was analyzed in 89 patients with acute hepatitis B infection during 1976-1979 in Gothenburg, Sweden, and in 46 patients (16 drug addicts) with chronic HBsAg-positive liver disease. Four of the patients with acute hepatitis B had transiently detectable anti-δ antibodies in serum. At least three of these four cases were associated with intravenous drug abuse. Eleven of the HBsAg carriers (24) were anti-δ-positive, and all of them were drug addicts. One of the drug addicts transmitted hepatitis B infection without detectable anti-δ in serum to two other non-addicts via parenteral routes. Apparently, in Sweden today δ-infection is mostly restricted to drug addicts and seldom found in other groups of hepatitis B patients.

In vitro production of alpha interferon and gamma interferon was examined in cell cultures from 90 asymptomatic homosexual males and 19 healthy heterosexual male controls. The production of alpha and gamma interferon was significantly suppressed in homosexuals as compared to that in heterosexual controls (p < 0.005 and p < 0.001, respectively). Forty-one of the homosexuals produced less gamma interferon than any of the heterosexual controls. Antibodies against the human immune system virus (HIV) were found in eight homosexuals, who produced significantly less alpha and gamma interferon than did the HIV-seronegative homosexuals (p < 0.02). Neither carriage ofEntamoeba histolyticaorGiardia lamblianor serological evidence of infection with cytomegalovirus, Epstein-Barr virus or hepatitis B virus was associated with a significantly lower production of interferon than that found in homosexual males seronegative for these infections. No correlation was found between number of partners or practice of passive anal intercourse and production of interferons in homosexual men. It is concluded that the significantly lower production of both alpha and gamma interferon in asymptomatic homosexual males may play an important role in susceptibility to viruses, including HIV.

Summary Two types of morphological transformation of bovine kidney cells were obtained after inoculation with SV40. Primary cultures inoculated were transformed into cultures with epithelioid cells growing mainly in monolayer. When the kidney cells were subcultivated and infected at the 6th passage, another type of transformation, characterized by epithelioid and fibroblastic cells growing in a disorganized multilayer, was seen.

A method for assay of interferon activity based on the inhibition of virus yield in calf kidney cultures infected with poliovirus RNA is described. Evidence has been obtained for a linear relationship between the logarithm of the dilution of interferon and the logarithm of the virus yield suggesting a complex nature of the action of interferon. The RNA-interferon test was about 100 times more sensitive than other methods tested. This method also detected interferon in calf kidney cultures persistently infected with NDV.

Bacterial and animal viruses were inactivated by high voltage electrical discharges in water. The sensitivity of phages to the immediate component of this effect was correlated to the sensitivity to ultraviolet radiation. Transient electrical arcs in weak electrolytes also generated chemical compounds which were virucidal against phages T3, T5, and ϕX174 but were only slightly virucidal against phages T2 and T4.

Summary Among 466 hospitalized patients with serologically verified acute hepatitis B, 440 individuals (94.4%) could be followed up until normalization of liver function had occured, or for at least one year. In 90.2% of the patients followed-up liver function (including galactose tolerance) returned to normal within four months after onset of illness. Chronic persistent hepatitis (CPH) developed in 28 patients (6.4%) with persistence of hepatitis B surface antigen (HBs Ag) for at least one year in 14 patients (50%). Liver biopsy was performed in 20 of these 28 cases about a year after onset of illness and was consistent with CPH in all cases. Histological signs of chronic aggressive hepatitis developed in 15 patients (3.4%) and persistence of HBs Ag was observed in 11 of these patients (73%). No histological follow-up was performed in patients with normal liver function within four onths after onset of illness. Corticosteroid treatment in 56 patients with prolonged symptoms did not seem to predispose to persistence of HBs AG in the serum.

Eleven patients with disseminated midgut carcinoid tumour disease were subjected to hepatic artery embolisation. In six patients, lymphocytosis with a predominance of NK cells occurred and the cytotoxic activity of isolated lymphocytes increased. A relation between NK cell accumulation and subsequent radiological and biochemical response was observed, and it is suggested that anti-tumour mechanisms other than ischaemia may contribute to the therapeutic response in these patients.

RECENTLY it has been shown1that a virus isolated from cattle with signs of ‘mucosal disease’2is antigenically related to the virus of bovine virus diarrhœa3. In northern Sweden, a type of mucosal disease (‘Umeå disease’) was found to be accompanied or preceded by a respiratory disease. In paired serum samples from diseased animals increasing titres of antibodies were demonstrated against both bovine virus diarrhœa virus and para-influenza 3 virus4, but only para-influenza 3 virus was isolated5. The incidence of infections with bovine virus diarrhœa virus among Swedish cattle seems to be about 20 per cent as judged from the results of a serological survey in 1959–604. In the present work the properties on which Cooper6bases his classification of animal viruses have been investigated for bovine virus diarrhœa virus.

In a double-blind trial of hospital staff members at risk of contracting hepatitis B, 110 subjects received hepatitis B immune globulin or immune serum globulin prophylactically, An additional 125 individuals working in the same locations were unwilling to participate in the trial and received no prophylaxis. During the study period of 28 months, 13 cases of clinical hepatitis B occurred in the untreated group, whereas only three cases occurred among the subjects who received prophylaxis.