Biomedical subjects
Publications and source records attributed to H K Andersen.
Among 123 cadaveric renal allograft recipients transplanted in the period 1971-79, there were 18 with no evidence of past or present cytomegalovirus infection, 34 with primary infection and 71 with reactivated infection. One-year actuarial graft survival was 68%, 32% and 54%, respectively. The reasons for the better graft prognosis in the group without CMV infection were less rejection and fewer infections.
A solid-phase enzyme linked immunosorbent assay (ELISA) for determination of IgG antibodies to cytomegalovirus (CMV) is described. The assay used purified CMV and extracts of CMV infected cells as antigen. Antigens were desiccated onto the bottom surface of polystyrene microcuvettes. The antibodies bound to the antigens were assayed by anti-IgG-alkaline phosphate conjugate followed by addition of the enzyme substrate. Titration curves have been obtained from the sera of 35 blood donors and of 23 patients. Comparison of results obtained by ELISA with those obtained by complement fixation (CF) shows that there is agreement between the tests. Both purified CMV and extracts of CMV infected cells were found to be suitable antigens. Purified CMV was of value particularly in those sera which show high reactivity against control antigen. The ELISA technique described is approximately 412 to 548 times more sensitive than the CF test when purified CMV or extracts of CMV infected cells, respectively, are used as antigens. No significant heterotypic rise to CMV was observed by ELISA in three sets of sera with seroconversion to herpes simplex virus. The ELISA technique gives objective results, is easily performed, and may be adaptable as a routine test both for serological diagnosis of CMV infection and for screening of the general population.
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Thirty-nine renal allograft recipients who had received continuous immunosuppression for six to 13 years were examined clinically and virologically for evidence of past or present viral infection. Twenty-five had common warts, usually on the hands. In most the warts had appeared about one year after transplantation; once present, they never disappeared. Six patients had had a zoster rash from two months to four years after transplantation. None had had jaundice, and there was no change in the frequency of colds or non-specific fibrile illness. Four patients had no cytomegalovirus complement-fixing antibodies throughout the observation period; in the other 35 the antibody titre had risen appreciably during the first three to four months after transplantation. Antibody titres were high (mean 64) at follow-up, being only slightly lower than the highest titres achieved during the immediate postoperative period. None of the patients had had symptomatic cytomegalovirus infection, and in only two was the virus isolated from the urine at follow-up; the titres were extremely low. No changes occurred in the frequency of herpes simplex eruptions. Although all patients had herpes simplex humoral antibody, none excreted the virus. Although cytomegalovirus antibody titres were high, virus excretion was rare, indicating that chronic cytomegalovirus infection in these patients is immunologically well controlled.
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Screening of 3060 neonates for congenital cytomegalovirus (CMV) infection by virus excretion in the urine showed an overall incidence of 0.4%. The incidence was about 1% for mothers between 16 and 25 years and only 0.2% for mothers between 25 and 35. No mothers over 35 years of age gave birth to congenitally infected infants. The percentage of women in the child-bearing age susceptible to CMV infection was estimated by the absence of CMV complement-fixing antibodies in cord sera and ranged from 48% to 33% with increasing age. None of the infected infants showed obvious signs of congenital CMV infection at birth. At follow-up, two infants showed slight, but transient symptoms compatible with a foetal infection; a pair of premature twins exhibited retarded physical and psychomotor development, but this could just as well be ascribed to the prematurity itself. None of the infants had detectable CMV--IgM antibodies in cord sera, but a trend towards elevated total IgM concentration in cord sera and elevated virus excretion titres appeared in the infants with symptoms. With the very low incidence and no signs of sensomotor sequelae the preliminary conclusion is that foetal CMV infection in our population by no means has a significance to deserve screening or a vaccination programme.
Cell-mediated immunity to herpes simplex virus and cytomegalovirus, using the lymphocyte transformation test and interferon induction in lymphocytes, was studied in 59 patients from 1 day to 7 years after allotransplantation and compared with the results in normal subjects. Both parameters were permanently depressed with regard to cytomegalovirus. With herpes simplex virus, interferon production was also permanently depressed, whereas the transformation reaction was normal during the first year after transplantation and only slightly depressed in patients more than 1 year after transplantation. In 6 patients the above-mentioned assays and the complement fixation reaction were performed serially and related to the clinical signs of herpes simplex virus and cytomegalovirus infection. The relationship between depression of the transformation reaction and interferon production in lymphocytes and the occurrence of clinically evident herpes simplex virus and cytomegalovirus infections was, however, equivocal. The humoral immune response to herpes simplex virus was measured by the complement fixation test and the more sensitive antibody-dependent, cell-mediated cytotoxicity reaction, and a good correlation was found between these two tests, although only a few persons were found to be negative in the antibody-dependent, cell-mediated cytotoxicity reaction. The suggestion is made that only a few adults are "true" herpes simplex virus seronegative.
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The reactivity of human smooth-muscle antibodies (SMA) with F- and G-actin was investigated by means of an enzyme-linked immunosorbent assay (ELISA). Polystyrene tubes were coated with F-actin, G-actin and tropomyosin. The optimal reactivity of SMA with F-actin was achieved with tubes coated with actin concentrations in the range of 10-100 mug/ml, while both lower and higher amounts yielded lower reactivity. The reactivity with G-actin was low and only a little higher than the reactivity with tropomyosin or uncoated tubes, but much lower than the reactivity with F-actin. The differences in reactivity of SMA with F- and G-actin could not be explained by differences in binding of the two forms of actin to the tubes, although 1.7-2.5 times more F-actin than G-actin bound to the polystyrene surface after coating with equivalent amounts of protein. SMA-negative sera did not react with F-actin coated tubes indicating that the binding of antibody was not due to non-immunological binding of immunoglobulins. Human SMA thus react better with F- than with G-actin.
Lymphocytes from healthy adult individuals were examined for their ability to incorporate thymidine in the presence of cytomegalovirus (CMV) and dense bodies. It was found that lymphocytes from donors with antibodies to CMV were stimulated to incorporate thymidine-14C both by preparation of CMV and CMV dense bodies. Lymphocytes from CMV seronegative donors did not respond. Dilution experiments and the dose-response curve indicate that the stimulation induced by the dense body preparation was not caused by the small amounts of contaminating CMV particles. These results indicate that in healthy human adults there is a correlation between CMV seropositivity and in vitro lymphocyte transformation, induced by either CMV or by dense bodies.
Congenitally athymic nude (nu/nu) mice of a BALB/c genetic background were found considerably more resistant to the induction of focal necrotic hepatitis by herpes simplex virus type 2 (HSV-2) tha, were phenotypically normal littermates (nu/+) or BALB/c mice. The augmented resistance was age dependent, as it was only manifested in mice from 4 to 5 weeks of age. Studies of the course of infection showed that nude mice were able to restrain virus multiplication in the liver far better than normal mice in the early phase of infection. However, they seemed inferior to normal mice in eliminating the infectious process. In vitro investigation of peritoneal macrophages revealed that macrophages from 6-week-old nude mice exhibited accelerated spreading and were three times as restrictive in the replication of HSV-2 as macrophages from normal mice. However, no difference was found in the efficiency of adsorption/phagocytosis between macrophages from nude and normal mice. The increased resistance of nude mice could be abolished by blockade of the microphage function of the mice by silica. Nude mice reconstituted at birth with thymus cells were just as susceptible to infection as normal mice. These data suggest that the increased resistance of nude mice to HSV-2 hepatitis is due to the presence of nonspecifically activated macrophages before infection.
Among 17 patients with cytomegalovirus (CMV) infection smooth-muscle antibodies (SMA) of the IgM class were detected in 9 (53%) and IgG-SMA in 6 (35%), while no IgA-SMA were found. IgM-SMA were present most often and in the highest titres (10-160) in the beginning of the disease, while IgG-SMA were found both early and late during the course of infection. SMA occurred most frequently in patients with specific CMV antibodies of the IgM class and in patients with elevated serum alanine aminotransferase values, but these relationships were not significant. Elevated levels of serum IgG, IgA and IgM were found in CMV infection, and a correlation between serum IgM values and IgM-SMA titres was demonstrated (alpha less than 0.01). A similar correlation between serum IgG and IgG-SMA could not be established. These findings are in support of the assumption that IgM-SMA account for a minor part of the elevated serum IgM levels in CMV infection, but not of the hypothesis that the stimulus for antibody production is the release of antigens from liver cells.
The role of macrophages in the difference in liver pathogenicity between herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in mice was investigated by selectively blocking the macrophage function of the mice by silica. Intravenous administration of 3 mg of silica 2 h before virus inoculation partially abolished the difference between the two virus types, as judged by macroscopic and microscopic examination of the livers and by virus isolation studies. Intraperitoneal inoculation of 50 mg of silical before virus seemed more effective in suppressing the macrophage function, since this treatment almost completely eliminated the difference in hepatotropism between HSV-1 and HSV-2 as assessed by the number and size of the lesions appearing in the liver. The final outcome of the infection, death from encephalitis, was, however, not influenced by macrophage blockade.
Crude cytomegalovirus (CMV) antigen and purified CMV antigen were used in tests for complement-fixating (CF) antibodies in sera from 7 patients with CMV infection. CF antibodies to purified CMV appeared later than the other CF antibodies tested and parallel to neutralizing antibodies.
Antibodies against cytomegalovirus-specific early antigens (CMV-EA) were followed in sera, obtained from fifteen immunosuppressed renal-allograft recipients. Eight patients (sixty-two sera) showed seroconversion 47--137 days post-transplantation. Five patients (forty sera) with CMV antibodies at the moment of renal implantation all showed CMV-EA antibody rises. Two patients remained seronegative until 4 years after transplantation. Thus, in immunosuppressed patients, antibodies against CMV-EA remained a high titres during many years (4--8 years) after transplantation as distinct from the apparently transient nature in acutely infected previously healthy adults with CMV mononucleosis or post-perfusion syndrome. These results support the view that CMV-EA antibodies reflect an active viral proliferation in the host.
By means of the indirect immunofluorescent method, smooth-muscle antibodies (SMA) were detected significantly more often in patients with malignant diseases (11.7%) than in normal controls (3.3%) (0.02 greater than pgreater than 0.01). SMA occurred in 23.8% of patients with Hodgkin's disease, in 13.3% of patients with myeloproliferative diseases and in 4.7% of patients with lymphoproliferative diseases. Other tissue antibodies were rare and they were found to occur at the same frequency in patients and controls. The occurrence of cytomegalovirus (CMV) antibodies did not differ significantly in patients and controls and, in both groups, the frequency of these antibodies increased with increasing age. The frequency of Epstein-Barr-virus (EBV) antibodies increased also with increasing age both in patients and controls, but these antibodies were found more frequently in patients than in controls (p=0.03). No relationship between the occurrence of SMA and viral antibodies was demonstrated. Thus, the development of SMA in patients with malignancies could not be shown to be due to CMV or EBV infection.
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Sera from patients with Kaposi's sarcoma (KS) were examined for antibody titres to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV) types 1 and 2 by four techniques: indirect haemagglutination (IHA), complement fixation (CF), virus neutralization (NT) and indirect immunofluorescence (IF). The patients were classified, according to the stage of disease, as progressive and regressive. Control sera were obtained from healthy adults, matched for age, sex, race, socioeconomic status and geographic location, as well as from patients with melanoma, some of whom were receiving chemotherapy similar to that given to the KS patients. All KS sera contained CMV-neutralizing antibodies. Seventy-five percent of the European KS patients, mainly regressors, showed elevated anti-CMV titres by IHA with a significant increase in the geometric mean over the corresponding healthy adult group and the melanoma group. An overrepresentation of high anti-CMV titres, although less marked, was found by CF. There was no significant association with antibodies to EBV, HSV-1 and HSV-2 related antigens. By contrast, the African KS patients, mainly progressors, did not show a serologic association with CMV or with EBV and HSV-1 and 2. The implication of these results is discussed.