Histamine: a novel approach to cancer immunotherapy

The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties of histamine, a biogenic amine. Histamine inhibits ROS formation in MO via H2-receptors; thereby, histamine protects NK cells from MO-mediated inhibition and synergizes with IL-2 and IFN-alpha to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adjunct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.     

Mother to infant transmission of hepatitis C virus infection

Eight women with chronic hepatitis C virus (HCV) infection during pregnancy gave birth to 11 children. Five of these children had elevated ALT, but only two had increased levels in more than one sample. All children tested before 6 months of age were positive for anti-HCV at most up to 7 months of age and then became negative. One child with a maximum ALT level of 8.4 mukat/l however, regained anti-HCV positivity at 12 months of age, and a liver biopsy at 21 months of age showed resolving hepatitis. Passively acquired HCV antibodies are obviously found in newborns of anti-HCV-positive mothers with chronic hepatitis. In 1 of 11 children, active anti-HCV production and concomitant liver disease suggested mother to infant transmission of hepatitis C virus infection.     

The lack of transmission of NANB/C hepatitis between acute and chronically infected patients and their heterosexual partners

In order to study the risk of heterosexual transmission of non-A, non-B/C (NANB/C) hepatitis, 34 spouses and/or sexual partners to 34 index patients (13 women, 21 men; median age 39 years) with acute NANB/C hepatitis (anti-HCV positive 13/34) were repeatedly tested for antibodies to hepatitis C virus (anti-HCV) and serum alanine aminotransferase (S-ALAT) values. Spouses and/or sexual partners to 13 patients with chronic NANB/C hepatitis (11/13 anti-HCV positive) were also studied by determining anti-HCV and S-ALAT levels. No conclusive evidence of heterosexual transmission of NANB/C hepatitis was found.     

Outcome After Trans-tibial Amputation for Vascular Disease

All 112 patients (55 females and 57 males) with a primary unilateral trans-tibial amputation for vascular disease performed in one year at all five hospitals in Malmöhus county, Sweden were examined at 6 months according to the prosthetic function and prospectively followed-up 8 years after the amputation for survival, and prosthetic fitting. The prosthetic function was re-examined among the survivors 8 years postoperatively. At 6 months 50% were fitted with a prosthesis and later (up to 8 years) a further 13%, in total 32 females and 39 males. The mortality at 6 months was 33%, at 2 years 47% and at 8 years 92%. Age at amputation (p = 0.015), to be amputated on the left leg (p = 0.0004), to be able to walk alone outdoors before the amputation (p = 0.007) and not using a wheelchair (p = 0.02) were all found to be statistically significant predictors for receiving a prosthesis. Predictors for good function with the prosthesis 6 months postoperatively was male sex (23 of 57 vs 8 of 55 females) (p = 0.006) and greater ability to walk alone outdoors before the amputation (p = 0.01). There was no significant age difference in this comparison. The finding that it is more favourable to be amputated on the left leg merits further study.     

Histamine inhibits neutrophil NADPH oxidase activity triggered by the lipoxin A4 receptor-specific peptide agonist Trp-Lys-Tyr-Met-Val-Met

The vasoactive amine histamine is found at high concentrations in the immune and inflammatory tissues. Earlier studies have revealed that histamine regulates the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent formation of oxygen radicals by phagocytic cells. However, the effects of histamine on intracellular signal transduction mechanisms of relevance to oxidase regulation remain controversial. For this study, we investigated the effects of histamine on NADPH oxidase activity in human neutrophil granulocytes triggered by a lipoxin A4 receptor agonist [the hexapeptide Trp-Lys-Tyr-Met-Val-Met (WKYMVM), a formyl peptide receptor (FPR) agonist (the chemotactic tripeptide formylmethionyl-leucyl-phenylalanine (fMLF)) and an activator of protein kinase C (phorbol myristate acetate (PMA)]. We report that histamine, acting via H2-type histamine receptors (H2R), suppresses NADPH oxidase-dependent formation of oxygen radicals induced by WKYMVM and fMLF but not that induced by PMA. Peptide-induced mobilization of granule-localized complement receptor 3 (CR3) was unaffected by histamine suggesting that the inhibition specifically affected NADPH oxidase activation. Our data suggest that histamine downregulates FPRL1- and FPR-induced NADPH oxidase activity upstream of protein kinase C (PKC) and downstream of the separation of the peptide-induced signal into granule secretion and oxidase activation.     

Accumulation of natural killer cells after hepatic artery embolisation in the midgut carcinoid syndrome.

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.     

Hepatitis B vaccination with short dose intervals — A possible alternative for post-exposure prophylaxis?

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.

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Hepatitis-B-Impfung mit kurzen Applikationsintervallen — mögliche Alternative für die Prophylaxe nach Exposition?

Zusammenfassung Um die Antikörperantwort nach Hepatitis-B(HB)-Impfung zu beschleunigen, wurden die Impfstoffinjektionen bei einer Gruppe von Medizinstudenten in erheblich kürzeren Abständen vorgenommen, als üblicherweise empfohlen wird. Die Applikation der rekombinanten HB-Vakzine (Merck Sharp & Dohme) erfolgte zum Zeitpunkt 0, 2 und 6 Wochen (27 Geimpfte) oder nach dem für die Prä-Expositionsprophylaxe für HB empfohlenen Schema (0, nach 1 und 6 Monaten) (26 Geimpfte). Die Dosis betrug jeweils 10 µg des Impfstoffs. Bei Anwendung des Applikationsschemas mit kurzen Dosierungs-intervallen waren zwei Wochen nach der zweiten Impfdosis signifikant häufiger protektive Antikörperspiegel (10 IU/1) nachzuweisen (48% gegenüber 4%; p<0,001); alle nach diesem Schema Geimpften hatten innerhalb von zwei Monaten (d. h. zwei Wochen nach der dritten Dosis) serokonvertiert. Bei dem empfohlenen Applikationsschema kam die Antikörperproduktion langsamer in Gang, erreichte aber nach Gabe aller drei Dosen signifikant höhere Antikörper-Spitzenspiegel (p<0,001). Mit einer Impfstoffapplikation in kürzeren Zeitabständen läßt sich folglich beim Menschen die Bildung protektiver Antikörperspiegel gegen Hepatitis-B-Virus (HBV) beschleunigen. Dieses Impfschema mit kurzen Dosierungsintervallen, das sich in der Prophylaxe nach Exposition bei Schimpansen bewährt hat, sollte eventuell auch beim Menschen als Schema für die Prophylaxe nach Exposition erwogen werden, beispielsweise nach versehentlicher Exposition gegenüber mit HBV kontaminiertem Blut.

     

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.     

Long-term follow-up of chronic hepatitis non-A,non-B – with special reference to hepatitis C

ABSTRACT— One hundred and twenty-seven patients with histologically verified chronic non-A, non-B hepatitis were followed for up to 23 years (mean 6.3 years). Thirty-nine were infected by blood transfusion, 58 were drug-addicts and 30 had no obvious source of infection. Chronic persistent hepatitis (CPH) was diagnosed in 84 (66%), while 43 patients (34%) had chronic active hepatitis (CAH) with or without cirrhosis. Patients with CPH were significantly younger (29.7 years vs 46.8 years; p<0.01), irrespective of the type of virus exposure. Antibodies to hepatitis C virus (anti-HCV) were detectable in 91 patients (72%) and 36 (28%) were anti-HCV negative. Fifteen patients with acute onset, and negative for anti-HCV at the start, became positive during follow-up; 12 of them within 4.5 months. We found no differences among anti-HCV positive and anti-HCV negative patients in liver function tests, resolving rate, morphological progression in serial biopsies or mortality rate. Five previously anti-HCV positive patients became negative during follow-up and in two of them this was accompanied by decreasing hepatic inflammation.     

Interferon and natural killer cells in systemic lupus erythematosus.

Natural killer (NK) cell activity against several types of target cells was found to be subnormal in patients with systemic lupus erythematosus (SLE). Interferon (IFN) boosted the NK activity of cells from SLE patients to a significantly lesser degree than cells from normal controls. The production of IFN after stimulation of blood cells with Sendai virus was significantly decreased in SLE patients with active disease, and in a substantial proportion of the patients the production of phytohaemagglutinin (PHA)-induced IFN was below normal limits. Although the production of virus-induced IFN was clearly inversely correlated to disease activity no such correlation was observed for PHA-induced IFN. Serum levels of both pH2 stable and pH2 labile IFN were significantly higher in SLE patients than in controls. The findings clearly show that SLE is associated with abnormalities in the NK cell-IFN system but it cannot be stated whether these abnormalities are causally related to the development of disease or are secondary to pathological changes in SLE.