Svante Hermodsson

Mother-to-infant transmission of hepatitis C virus

OBJECTIVE To describe the rate of perinatal transmission of hepatitis C virus (HCV). DESIGN Follow-up study of newborn children of mothers with chronic HCV infection. SETTING A university hospital in Sweden. PARTICIPANTS Fourteen women with chronic HCV infection and their 21 newly born children. MAIN OUTCOME MEASURES Detection of HCV RNA in serum by the polymerase chain reaction and detection of anti-HCV antibody by second generation assays. RESULTS All mothers were found to be positive for anti-HCV antibody both by second-generation enzyme-linked immunosorbent assay (ELISA) and by second-generation recombinant immunoblot assay (RIBA-2); all also had detectable serum HCV RNA. Two children had long-lasting alanine aminotransferase (ALT) elevations, and one of them became HCV RNA positive. None of the other children developed biochemical hepatitis. However, two additional children had temporary viremia. Only the child with biochemical and biopsy-proven hepatitis and detectable HCV RNA in multiple blood samples actively produced anti-HCV antibody. CONCLUSIONS Mother-to-infant transmission of HCV infection from chronically infected women without human immunodeficiency virus (HIV) infection seems to be uncommon.

Hepatitis C superinfection in hepatitis C virus (HCV)-infected patients transplanted with an HCV-infected kidney

Hepatitis C virus (HCV) genotypes, determined by polymerase chain reaction with type-specific primers, were studied in 5 already HCV-infected patients receiving kidneys from HCV-infected cadaver donors. Three patients were investigated retrospectively using stored pre- and posttransplantation sera and followed 18-28 months after transplantation. Two recipients with HCV genotype 2b infection had received kidneys from 1 genotype 3a-infected donor. In 1 recipient, HCV 2b was replaced by the donors type; in the other recipient, a prolonged mixed infection of 3a and 2b occurred. Persistent alanine aminotransferase (ALT) elevation (3- to 5-fold) appeared in both patients. The third patient, also HCV 2b infected when transplanted with an HCV 3a-infected kidney, remained infected with HCV 2b only. Two patients, one with HCV genotype 1b and the other with genotype 3a, were followed prospectively with frequent bleeds (initially biweekly) and genotyping over 14 months after they had received kidneys from 1 HCV genotype 1a-infected donor. The HCV 1b-infected recipient remained infected with 1b only and had minimal biochemical signs of liver injury. In the other recipient, mixed infection of 3a and 1a appeared at week 3 and persisted for several weeks, until only genotype 1a could be detected. This patient had elevated ALT levels before transplantation. After onset of mixed infection, ALT levels increased further for several weeks, and returned to pretransplantation levels when only HCV 1a was found. HCV-infected kidneys transplanted into HCV-infected recipients gave 3 different virus patterns. Most patients benefitted in the short term, but some super-infected patients experienced increased liver damage.

HISTAMINE PROTECTS T CELLS AND NATURAL KILLER CELLS AGAINST OXIDATIVE STRESS

Oxidative stress inflicted by monocytes/macrophages (MO) is recognized as an important immunosuppressive mechanism in human neoplastic disease. We report that two types of lymphocytes of relevance for protection against malignant cells, T cells and natural killer (NK) cells, became anergic to the T cell and NK cell activator interleukin-2 (IL-2) after exposure to MO-derived reactive oxygen metabolites and subsequently acquired features characteristic of apoptosis. The MO-induced anergy and apoptosis in T cells and NK cells were reversed by histamine, an inhibitor of reactive oxygen metabolite synthesis in MO. We propose that strategies to circumvent oxidative inhibition of lymphocytes may be of benefit in immunotherapy of neoplastic disease.

Enhancement of human natural killer cell cytotoxicity by serotonin: Role of non-T/CD16+ NK cells, accessory monocytes, and 5-HT1A receptors☆

Serotonin (10(-4) - 10(-7) M) augmented natural killer cell cytotoxicity (NKCC) of human CD16+/non-T lymphocytes in vitro against the NK-sensitive target cells K 562 erythroleukemic, Molt-4 lymphoma, Chang liver cells, and against EBV-transformed Daudi B-lymphoblastoid target cells by a mechanism of action involving a prostaglandin-and IL-1-independent accessory function of monocytes. No evidence for the production of intermediary, NK-enhancing cytokines by serotonin was obtained, suggesting a cell-to-cell-mediated interaction between monocytes and NK cells as a plausible mechanism of action for the NK-augmenting effect. Monocytes recovered by counter-current centrifugal elutriation but not monocytes recovered by adherence reconstituted the effect of serotonin when added to nonadherent NK cells. NK-enhancing effects of serotonin were mimicked by two 5-HT1A-type serotonin receptor agonists, 8-OH-DPAT and (+)-ALK. The development of NKCC in response to serotonin could be resolved into (i) an induction phase, dependent on the presence of accessory monocytes and serotonin, and (ii) an effector phase, independent of the presence of monocytes or serotonin. Serotonin-activated MNC continued to exert augmented cytotoxicity for at least 8 hr after the removal of serotonin and monocytes. In several experiments, serotonin-activated NK cells killed greater than 75% of K 562 target cells even at low effector to target cell ratios and low baseline NKCC. We suggest that serotonin may have a role in nonspecific tumor defence by regulating an earlier unrecognized interplay between monocytes and NK cells.

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.

Serotonin protects NK cells against oxidatively induced functional inhibition and apoptosis

High concentrations of the neurotransmitter serotonin can be found ininflamed and ischemic peripheral tissues, but the role of serotonin inimmunoregulation is largely unknown. Here we report that serotoninprotected human natural‐killer (NK) cells from oxidatively inducedinhibition inflicted by autologous monocytes in vitro. Serotoninprotected NK cells from monocyte‐mediated apoptosis and suppression ofcytotoxicity and maintained the activation of NK cells induced byinterleukin‐2 despite the presence of inhibitory monocytes. A detailedanalysis of these protective effects revealed that serotonin scavengedreactive oxygen species (ROS) derived from theH2O2‐myeloperoxidase (‐MPO) system. Serotoninshared this scavenger activity with its precursor, 5‐hydroxytryptophan(5‐HTP); however, serotonin was >10‐fold more potent than 5‐HTP inprotecting NK cells against functional inhibition and apoptosis. Wepropose that serotonin, by scavenging peroxidase‐derived ROS, may serveto protect NK cells from oxidative damage at inflammatory sites.

Risk Factor Exposure Among Hepatitis C Virus RNA Positive Swedish Blood Donors - The Role of Parenteral and Sexual Transmission

The potential modes of transmission for hepatitis C virus (HCV) infections were studied using a multivariate analysis of risk factor exposure among 51 2nd generation anti-HCV and HCV-RNA positive and matched anti-HCV negative blood donors. The following variables were found to be independently associated with anti-HCV and HCV-RNA positivity: intravenous drug use (IVDU) (p < 0.001), blood transfusion (p < 0.01), tattoos (p < 0.001), previous hospitalization (p < 0.05), history of sexually transmitted disease (STD) (p < 0.001) and lack of travels outside of Europe (p < 0.05). Among the 23 HCV-RNA positive donors without a history of IVDU or blood transfusion, an increased frequency of hospitalization (p = 0.017) and history of STD (p = 0.023) were found. Five of 22 sexual partners of the 51 index blood donors were HCV-RNA positive and in one of these couples sexual transmission was suspected. Anti-HCV and HCV-RNA positive donors were more often seropositive for herpes simplex virus type 2 (HSV-2) antibodies than were HCV-negative controls (p = 0.015). Sexual transmission of HCV may occur, but the possible role of HSV-2 requires further investigation.

Histamine in immunotherapy of advanced melanoma: a pilot study

Sixteen patients with advanced metastatic malignant melanoma were treated with a high-dose infusion of interleukin-2 (IL-2; 18×106 IU/m−2 day−1) together with daily subcutaneous (s.c.) injections of interferon α (IFNα; 3×106 U/m−2 day−1) in 5-day cycles. Nine of these patients were given histamine (1 mg s.c.) twice daily during treatment with IL-2 and IFNα. In the seven patients who did not receive histamine, one partial response (that is a reduction of more than 50% in the total tumour burden) was observed in a patient with skin and lymph node melanoma. In the eight histamine-treated patients evaluable for response, four partial responses were observed. Two other patients showed regression at one site of metastasis but tumours remained unchanged at other sites. Two histamine-treated patients showed complete resolution of extensive liver metastasis. Sites of response in histamine-treated patients also included the subcutis, lymph nodes, skeleton, spleen and muscle. Lung melanoma did not respond to histamine/IL-2/IFNα. Three patients with lung tumours responded with significant (more than 50%) reduction of the volume of soft-tissue tumours, suggesting that the response to histamine may be organotropic. Survival was significantly prolonged in patients receiving histamine. Our data suggest that treatment with histamine may improve the antitumour efficacy of immunotherapy in metastatic melanoma.

Intradermal, Subcutaneous or Intramuscular Administration of Hepatitis B Vaccine: Side Effects and Antibody Response

The immune response after vaccination with a plasma-derived hepatitis B unit vaccine (MSD) administered intradermally or subcutaneously in 2 microgram doses was compared to the recommended 20 microgram dose administered intramuscularly. The trial was performed in 58 healthy volunteers 20-43 (mean 30) years old. No statistically significant difference in seroconversion rate was observed when the intradermal (i.d.) (2 micrograms) and intramuscular (i.m.) (20 micrograms) routes were compared (100% and 96% seroconversion, respectively). The 2 microgram dose administered subcutaneously gave a seroconversion rate of only 63%. The intradermal and i.m. routes also gave significantly higher mean titers of anti-HBs than the subcutaneous route (p less than 0.005). No severe reactions occurred and local reactions were seen almost exclusively in those vaccinated intradermally. These reactions included mainly discoloration, itching and nodule formation at the site of injection. The intradermal route ought to be considered for administration of hepatitis B vaccine since the dosage can be reduced to 1/10 without affecting the antibody response. Correct intradermal deposition of the vaccine is, however, crucial for an adequate immune response. This is probably the main disadvantage if large-scale vaccination programs should be carried out in developing countries using i.d. immunization.

Histamine: A Novel Approach to Cancer Immunotherapy

Abstract 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-α (IFN-α) 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-α to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties ofhistamine, 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-α 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-α is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.