An immunopharmacological analysis of adrenaline-induced suppression of human natural killer cell cytotoxicity

The circulating catecholamine adrenaline effectively suppressed human natural killer cell cytotoxicity (NKCC) when added to mixtures of effector lymphocytes and 51Cr-labelled target cells in a 4-hour 51Cr release assay in vitro. The effect was mimicked by the beta 2-receptor agonist terbutaline but not by the beta 1-receptor agonist prenalterol or the alpha 1/alpha 2-receptor agonist clonidine. Adrenaline-induced NKCC suppression was completely and potently antagonized by the mixed beta 1/beta 2-receptor antagonist propranolol and the selective beta 2-receptor antagonist ICI 118,551 but not by the beta 1-selective antagonist metoprolol. By comparing the adrenaline sensitivity of high-density (HD) and low-density (LD) lymphocytes, fractionated by Percoll density gradient centrifugation, we found that HD cells appeared more sensitive to adrenaline-induced suppression than LD cells. In both types of effector cells, adrenaline significantly suppressed NKCC at a final concentration of 10(-11) M. Pretreatment of LD effector cells with IFN-alpha reduced the NKCC suppression by subsequent adrenaline treatment. Pretreatment with recombinant IL-2 virtually abolished the response to adrenaline. This effect was noted also when IL-2 and adrenaline were incubated simultaneously during the 4-hour 51Cr release assay. Our data suggest a role for adrenaline, via lymphocyte beta 2-receptor activation, in the regulation of natural killer cells.     

The development of coxarthrosis. A radiological follow-up of patients operated upon

It is necessary to distinguish between coxarthrosis and age-related changes, as the latter are not signs of disease. Cartilage destruction is the earliest definite radiological sign of arthrosis. The femoral head is displaced when cartilage destruction and secondary osseous changes have reached an advanced stage. This implies a circulus vitiosus and an acceleration of the arthrotic process. Coxarthrosis can be divided into two types, medial and cranial. The size of the CE angle (see Fig. 1) is of decisive importance for the type of coxarthrosis to be developed. The present study demonstrates that coxarthrosis is as a rule of a secondary nature, the aetiology being pre-arthrotic deformities that cause abnormal load conditions in the hip joint. Synovitis plays an important role in the pathogenesis in many cases.     

Humoral immunoreactivity in chronic active hepatitis: relation to HLA antigens.

43 patients with chronic active hepatitis (CAH) exhibited significantly higher levels of antibodies against measles and polio type 2 und 3 when compared to 43 age- and sex-matched healthy controls. No significant differences were found for antibodies against polio type 1, rubella, herpes simplex, mumps virus, and tetanus. There was no correlation between antibody levels and the presence of HLA-B8 and/or HLA-B12. The antibody response to vaccination with polio vaccine (killed) and tetanus toxoid was not higher in CAH patients carrying HLA-B8 and/or HLA-B12 than in patients without these antigens. The results indicate that CAH is associated with an increased immunoreactivity, which is, however, not linked to HLA-B8 and/or HLA-B12.     

The long-term outcome of hepatitis B

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 (HB_s 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 HB_s 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 HB_s AG in the serum.

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Langfristige Folge der Hepatitis B

Zusammenfassung Von insgesamt 466 stationären Patienten mit serologisch verifizierter akuter Hepatitis B konnten 440 (94,4%) bis zur Normalisierung der Leberfunktion oder mindestens ein Jahr nachbeobachtet werden. Bei 90,2% der nachbeobachteten Patienten normalisierte sich die Leberfunktion (einschließlich Galaktosetoleranz) binnen 4 Monaten nach Ausbruch der Krankheit. Chronisch persistierende Hepatitis entwickelte sich bei 28 Patienten (6,4%) mit Persistenz des Hepatitis-B-Oberflächenantigens (HB_S AG) für die Dauer von mindestens einem Jahr bei 14 Patienten (50%). Bei 20 dieser 28 Fälle wurde ungefähr ein Jahr nach Ausbruch der Krankheit eine Leberbiopsie durchgeführt, die in allen Fällen dem Bild der chronisch persistierenden Hepatitis entsprach. Histologische Zeichen der chronisch aggressiven Hepatitis entwickelten sich bei 15 Patienten (3,4%) und bei 11 von ihnen (73%) wurde Persistenz des HB_sAg festgestellt. Bei Patienten mit normaler Leberfunktion binnen 4 Monaten nach Ausbruch der Krankheit wurde keine histologische Kontrolluntersuchung vorgenommen. Die Kortikosteroidbehandlung von 56 Patienten mit langfristigen Symptomen schien nicht für die Persistenz von HB_s AG im Serum zu prädisponieren.

     

Serotonin protects NK cells against oxidatively induced functional inhibition and apoptosis.

High concentrations of the neurotransmitter serotonin can be found in inflamed and ischemic peripheral tissues, but the role of serotonin in immunoregulation is largely unknown. Here we report that serotonin protected human natural-killer (NK) cells from oxidatively induced inhibition inflicted by autologous monocytes in vitro. Serotonin protected NK cells from monocyte-mediated apoptosis and suppression of cytotoxicity and maintained the activation of NK cells induced by interleukin-2 despite the presence of inhibitory monocytes. A detailed analysis of these protective effects revealed that serotonin scavenged reactive oxygen species (ROS) derived from the H(2)O(2)-myeloperoxidase (-MPO) system. Serotonin shared this scavenger activity with its precursor, 5-hydroxytryptophan (5-HTP); however, serotonin was >10-fold more potent than 5-HTP in protecting NK cells against functional inhibition and apoptosis. We propose that serotonin, by scavenging peroxidase-derived ROS, may serve to protect NK cells from oxidative damage at inflammatory sites.     

NK cell-mediated killing of AML blasts: role of histamine,monocytes and reactive oxygen metabolites

Abstract: Blasts recovered from patients with acute myelogenous leukaemia (AML) were lysed by heterologous natural killer (NK) cells treated with NK cell-activating cytokines such as interleukin-2 (IL-2) or interferon-α (IFN-α). The cytokine-induced killing of AML blasts was inhibited by monocytes, recovered from peripheral blood by counterflow centrifugal elutriation. Histamine, at concentrations exceeding 0.1 μM, abrogated the monocyte-induced inhibition of NK cells; thereby, histamine and IL-2 or histamine and IFN-α synergistically induced NK cell-mediated destruction of AML blasts. The effect of histamine was completely blocked by the histamine H2-receptor (H2R) antagonist ranitidine but not by its chemical control AH20399AA. Catalase, a scavenger of reactive oxygen metabolites (ROM), reversed the monocyte-induced inhibition of NK cell-mediated killing of blast cells, indicating that the inhibitory signal was mediated by products of the respiratory burst of monocytes. It is concluded that (i) monocytes inhibit anti-leukemic properties of NK cells, (ii) the inhibition is conveyed by monocyte-derived ROM, and (iii) histamine reverses the inhibitory signal and, thereby, synergizes with NK cell-activating cytokines to induce killing of AML blasts.     

Interleukin-2 can induce suppression of human natural killer cell cytotoxicity.

By interaction with monocytes, interleukin-2 (IL-2) suppressed natural killer (NK) cell cytotoxicity (NKCC) of human, Percoll-fractionated, low-density mononuclear cells. The NK-suppressive effect of IL-2 was independent of de novo formation of prostaglandins or protein since it was unaffected by treatment with indomethacin and cycloheximide, respectively. A monoclonal antibody to the p55 (beta) moiety of the IL-2 receptor (anti-Tac/anti-CD25) blocked IL-2-induced NKCC suppression but did not affect the NK-enhancing effect of the lymphokine. We conclude that IL-2 exerts a monocyte-dependent, IL-2 beta-receptor mediated suppressive influence on human NK cells.     

Liver morphology in acute viral hepatitis related to the hepatitis B antigen

The liver histology in infectious hepatitis or hepatitis A (HA) and serum hepatitis or hepatitis B (HB) is generally described as identical. However, the clinical separation of the two types has been a problem. Today a serological reaction based on the well documented association between hepatitis antigen and HB is of great assistance in the differential diagnosis. The present study of 165 hepatitis cases separated into hepatitis A and B by this test method indicates quantitative differences in the liver histology of the two types. Thus HB was associated with more prominent parenchymal cell damage and Kupffer cell reaction, while intrahepatic cholestasis was found in a significantly higher frequency in cases presumed to represent HA.The presence of intrahepatic cholestasis was associated with higher levels of serum bilirubin but otherwise no correlation was found between liver morphology and biochemical liver tests.The patients included a group of young intravenous amphetamine addicts with HB. No differences of importance were found histologically in addicts and other patients with hepatitis B.     

Synergistic activation of human natural killer cell cytotoxicity by histamine and interleukin-2

Interleukin-2 (IL-2) is recognized as a major activating signal for human natural killer (NK) cells. The presence of monocytes alters NK cell responsiveness to IL-2. Thus, while IL-2 effectively augments NK cell cytotoxicity (NKCC) in monocyte-depleted NK effector cells, it is relatively ineffective or even suppressive for NK cells in monocyte-containing, NK-cell-enriched mononuclear cell fractions. Here we report that concomitant treatment with IL-2 and the biogenic amine histamine synergistically augmented NKCC against K562 and Daudi target cells of CD3-/CD16+ human NK cells in the presence but not in the absence of monocytes. Addition of peripheral-blood monocytes, recovered by countercurrent centrifugal elutriation, to purified NK cells abrogated IL-2 induced NK cell activation, reconstituted the synergistic, NK-activating effects of histamine and IL-2, and strongly reduced baseline NKCC. The effects of histamine on baseline NKCC and on NK cell responsiveness to IL-2 were related to counteraction of monocyte-mediated NK cell suppression. By contrast, histamine did not affect baseline or IL-2-induced NKCC in mixtures of NK cells and monocytes when the latter cells were recovered after adherence. The effect of histamine on NK cell responsiveness to IL-2 was mediated by H2-type histamine receptors, as judged by mimicry exerted by the specific H2 receptor agonist dimaprit, but not by an H2-receptor-inactive derivative of this compound, N-methyldimaprit, and blocking by the H2 receptor antagonist ranitidine. Experiments in which monocytes and nonadherent NK cells were separately pretreated with ranitidine prior to histamine treatment suggested that NK-regulatory effects of histamine were mediated by H2 receptors on monocytes. Our data suggest that histamine may provide an important signal in the regulation of NK cell responsiveness to IL-2.     

Hepatitis B Antigen and Prevention of Post-Transfusion Hepatitis B

Abstract. Screening for hepatitis B antigen (HB_sAg) in the serum of blood donors and exclusion of antigen-positive blood units have reduced the frequency of post-transfusion hepatitis but several cases of hepatitis B still occur in association with transfusions. One explanation for this is probably that HB_sAg is not an indicator of infectivity. Thus healthy carriers of the antigen seem to have low infectivity while carriers with chronic liver disease as well as donors incubating hepatitis B probably present a great risk.