A phase I trial of recombinant human interferon-γ in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS)

A Phase I study of recombinant interferon-gamma (rIFN-) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m² of rIFN-. rIFN- was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m² group revealed that peak serum levels of up to 153 U/ml occurred 2–4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7–12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m² but suppressed at 1.0 mg/m² of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1–1.0 mg/m² and that at least modest evidence of systemic immunomodulation may be seen when rIFN- is given at doses at or near this MTD.     

Sustained elimination of hepatitis B virus from serum induced in a patient with chronic hepatitis B and advanced human immunodeficiency virus infection

A 48-year-old male patient was admitted with acquired immunodeficiency syndrome (stage III, Centers for Disease Control 1993) and viremic hepatitis B. Blood CD4 count was 15/l. Discontinuation of prednisolone, previously prescribed by the patient's family practitioner because of elevated liver enzymes, resulted in severe hepatitis (alanine aminotransferase > 300U/1). Administration of interferon-, (9 × 10⁶U s.c. 3 × weekly) was initiated. Serum markers of viral replication disappeared, and aminotransferase levels returned to normal within a few weeks. The patient's serum was found negative for HBsAg after 3 months. Immunohistochemical analysis of liver biopsies before and during interferon therapy showed disappearance of all hepatitis B virus antigens and a marked reduction in inflammatory activity. Hepatitis B virus seroconversion remained stable until the patient died from the syndrome 2 years later. This case shows that in spite of severe HIV-associated immune deficiency with CD4 counts constantly below 100/l, interferon- can lead to sustained serological and histological improvement of viremic hepatitis B. Previous administration and discontinuation of cortisone may have helped to reach this effect.Abbreviations HBV hepatitis B virus - HIV human immunodeficiency virus - IFN interferon Correspondence to: G. Gerken     

Human T-lymphocyte subset production of immune (γ) interferon

Human T, T, and T lymphocyte subpopulations have the capacity to respond to phytohemagglutinin (PHA)in vitro with proliferation and the production of a pH 2 and heat-labile interferon. This occurs both when the subsets are isolated by direct rosetting techniques or by negative selection. Macrophages enhance the production of the interferon by each lymphocyte subset and do not themselves produce interferon in response to products of PHA-activated lymphocyte subsets. Thus our studies indicate that subpopulations of T lymphocytes known to differ with regard to morphology, surface receptors, RNA content, response to corticosteroids and X-irradiation, and other functional capabilities do not differ with regard to their capacity to produce interferon.     

Alterations in the half-life and clearance of IgG during therapy with intravenous γ-globulin in 16 patients with severe primary humoral immunodeficiency

Published studies of the metabolism of human IgG using trace amounts of radiolabeled IgG demonstrated that the elimination of native IgG followed first-order kinetics but that the half-life of IgG was shortest in patients with the highest serum concentrations of IgG. To evaluate the effect of increasing the serum concentration of IgG on the metabolism of IgG, we determined the half-life and clearance of IgG and tetanus antibody in 16 patients with severe primary humoral immunodeficiency diseases while they received several doses of intravenous -globulin (IVIG). Each patient received 100 mg/kg of IVIG each month and the half-life and clearance of IVIG were determined by following the decline in the serum IgG concentration. The dose of IVIG was adjusted to give a minimum IgG level of 200 mg/dl and the half-life was reevaluated. The dose was again adjusted to give minimum concentrations of 450 mg/dl and two additional studies were performed. Mean doses of IVIG infused increased from 100 to 346 mg/kg. The mean trough serum IgG concentration was 191 mg/dl on the standard dose and increased to 427 mg/dl at the highest dose. The serum half-lives of IgG were highly variable, ranging from 22 to 96 days. The mean decreased from 43 days in the first to 33 days in the third and fourth studies, and the clearances of IgG increased from 1.8339 to 2.4302 mg/kg/day, but the differences were not statistically significant. Patients with the highest serum IgG concentrations tended to have the longest half-lives, suggesting that intrinsic IgG production might falsely prolong the calculated half-life of IgG. However, it was possible to determine the half-life in these patients by measuring the decline in tetanus antibody. The half-life measured by this technique in the third and fourth studies was 27 and 36 days and the clearances were 2.988 and 3.648 ml/kg/day. Knowledge of the metabolism of IgG in these patients may lead to more appropriate guidelines for determination of dosage.     

Correlation between soluble serum CD16 (sCD16) levels and disease stage in patients with multiple myeloma

CD16, the type III receptor for IgG, is expressed on neutrophils, natural killer cells, and some T lymphocytes, mast cells, and activated monocytes but not on cells of the B-lymphocyte lineage including plasma cells. It is also produced in a soluble form found in serum. We analyzed sera from 165 multiple-myeloma patients, 29 patients with monoclonal gammopathies of unknown significance, and 20 normal disease-free donors. We found that the level of soluble CD16 was significantly decreased in sera from patients with multiple myeloma compared to sera from healthy and monoclonal gammopathies of unknown significance donors (P=0.0001). In addition, a stage-dependent decrease in soluble CD16 was observed, with a highly significant difference (P=0.004) between stage I and stage II+III myeloma patients. The correlation between the myeloma stage and the serum level of soluble CD16, which is related to the host response, was found to be more sensitive than that of ₂-microglobulin, which reflects the tumor burden. The concomitant evaluation of the serum levels of these two markers allows better staging and therefore has a more precise prognostic value.     

Enhancement of interleukin-2 and γ-interferon productionin vitro on cord blood lymphocytes andin vivo on primary cellular immunodeficiency patients with thymic extract (Thymostimulin)

Cord blood mononuclear cells (MNC) were isolated from 20 normal full-term newborns. These MNC were preincubated with either 50, 100, or 200 µg/ml Thymostimulin or without Thymostimulin. The interleukin-2 (IL-2) and -interferon (-IFN) production, cytotoxicity, and lymphoproliferation and IL-2 receptor (Tac) expression were all significantly increased after Thymostimulin treatment. For evaluation of thein vivo effect, two combined-imimunodeficiency patients defective on the thymic level, one with progressive BCG infection, and one with DiGeorge syndrome were used. Before Thymostimulin treatment, the patient's MNC did not produce sufficient amounts of IL-2 and -IFN. The cytotoxicity and lymphoproliferation were also low. After Thymostimulin treatment, the IL-2 and -IFN production, cytotoxicity, and lymphoproliferative response were enhanced. These results suggest that Thymostimulin may be beneficial in the clinical treatment of primary cellular immunodeficiency. The improved immune reactivity including cytotoxicity and enhanced IL-2 and -IFN production in the Thymostimulin treatment also indicates that there may be a beneficial effect on the combination of chemotherapy and Thymostimulin.     

Multicenter Crossover Comparison of the Safety and Efficacy of Intraglobin-F with Gamimune-N, Sandoglobulin, and Gammagard in Patients with Primary Immunodeficiency Diseases

The safety and clinical efficacy of a liquid, -propiolactone-stabilized intravenous -globulin, Intraglobin-F, was evaluated in a multicenter, double-blind study comparing Intraglobin-F to Gamimune-N, Sandoglobulin, or Gammagard. -Propiolactone stabilizes the IgG molecule to decrease aggregate formation and is a potent virucidal agent that reduces the risk of viral transmission by intravenous -globulin (IVIG) preparations. Twenty-seven patients with primary immunodeficiency diseases were enrolled at three centers. Each patient received 6 months of therapy with either Intraglobin-F or the IVIG preparation that they had received during the preceding 3 months, then crossed over to the other preparation. Twenty-three patients completed the study. One patient withdrew because of an adverse event, generalized urticaria. A second patient withdrew because of fatigue and perceived decreased efficacy. Adverse reactions were comparable and occurred in 8.7% of the infusions of Intraglobin-F and 6% of the infusions with Sandoglobulin. None were severe or life-threatening. There was no discernible difference in efficacy between any of the products. The number of days when patients noted symptoms in their diaries was similar for Intraglobin-F and the comparison preparations, 4158 vs 4143. Similarly, there were no differences in the number of physician visits (33 vs 22), days missed from work or school (405 vs 404), days with fever (41 vs 47), or days of prophylactic antibiotics (675 vs 642). There was an increase in the number of days when antibiotics were given therapeutically (578 vs 451); most of the difference was attributable to one patient. There also was a difference in the number of days of hospitalization (21 vs 0), but 19 of the days were accounted for by two patients. When the patients were asked to score their feeling of well-being on a scale of 1 to 5, with 1 being entirely well, the mean score for the patients on Intraglobin-F was 1.86 (range, 1.0 to 3.0), compared to 1.85 (range, 1.0 to 3.2) for patients while on the comparison preparations. Trough IgG levels were slightly lower during the period when patients were treated with Intraglobin-F compared to the other products. There were no abnormalities in blood chemistries or hematologic parameters. Thus, Intraglobin-F is comparable to three of the marketed IVIG preparations in efficacy and safety, as well as patient acceptability, and offers the additional benefit of an extra virucidal step to reduce further the risk of transmitting viral infections.     

Effect of immunization against rabies on γ-aminobutyric metabolism in the animal brain

Subcutaneous injection of fixed rabies virus into albino rats weighing 100–120 g is followed by a decrease in the-aminobytyric acid (GABA) concentration in the animals' brains. An increase in the activity of GABA--ketoglutarate transaminase also is observed in the brain tissue of animals vaccinated against rabies.Laboratory of Immunopathology, D. I. Ivanovskii Institute of Virology. Laboratory of Biochemistry, N. N. Burdenko Institute of Neurosurgery, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician V. D. Timakov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 2, pp. 184–185, February, 1976.     

Synergistic effects of tumour necrosis factor-α and interferon-γ on feline haemopoietic progenitors

Pathogenic mechanisms that underlie feline leukaemia virus subgroup-C (FeLV-C) induced erythroid aplasia are unknown. FeLV-C infection is associated with higher serum levels of interferon- (IFN-) and tumour necrosis factor- (TNF-), which may act synergistically to cause haemopoietic suppression. In the present studies, the synergistic effects of TNF- and IFN- on feline bone marrow progenitors in vitro were evaluated. Bone marrow mononuclear cells from specific-pathogen-free cats were exposed to TNF- (100 and 200 pg/ml) and IFN- (100 or 200 units/ml), alone or in combination, for 2 h before plating for clonal assays of colony forming units. Our results show that TNF- and IFN- in combination caused marked suppression of feline colony forming units-erythroid (CFU-E), burst forming units-erythroid (BFU-E), and colony forming units-fibroblasts (CFU-F), whereas colony forming units-granulocyte/macrophage (CFU-GM) were minimally affected. The same concentrations of TNF- and IFN- alone had minimal effects on CFU-E, BFU-E and CFU-F. These results suggest that TNF- and IFN- may play a significant role in regulating haemopoiesis in cats and may be involved in the pathogenesis of erythroid aplasia in cats infected with feline leukaemia virus.     

Prostagiandin E1 and F2 α levels during development of shock induced by plague toxin

Laboratory of the Molecular Basis of Pathogenesis of Infectious Diseases, Central Research Institute of Epidemiology, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. I. Pokrovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 105, No. 3, pp. 313–315, March, 1988.     

Action ofγ-aminobutyric acid and its phenyl derivative on central links of vascular reflexes from aortic-carotid chemo- and mechanoreptors

Experiments on decerebrate cats revealed an inhibitory effect of -aminobutyric acid (GABA; 100–200 g/kg) and its phenyl derivative, phenyl-GABA (20 mg/kg), on depressor responses of the systemic arterial pressure and on inhibition of spontaneous electrical activity in the renal nerve arising in response to excitation of the carotid sinus mechanoreceptors and afferent fibers on the sinus and depressor nerves carrying impulses from mechanoreceptors. Pressor responses of the systemic arterial pressure and electrical activity evoked in the renal nerve by stimulation of the carotid sinus chemoreceptors were intensified after administration of the same doses of GABA and phenyl-GABA. The results are interpreted from the standpoint of the depriming action of GABA and its phenyl derivative on the paramedian reticular nuclei of the medulla.Paper read at the March, 1974 Meeting of the Volgograd Scientific Society of Pharmacologists.Department of Pharmacology, Volgograd Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 79, No. 4, pp. 71–75, April, 1975.     

Induction of lymphokine-activated killer cells with low-dose interleukin 2 and interferon-γ in oral cancer patients

Lymphokine-activated killer (LAK) cells were induced with low-dose recombinant interleukin 2 (rIL-2) and recombinant interferon- (IFN-) in 28 oral carcinoma patients. The patients received daily intravenous injections of rIL-2 (1.2×10⁵ U/m²) and rIFN- (7.0×10⁴ U/m²), and both natural killer (NK) and LAK activities were periodically examined. A significant increase in CD16⁺CD57⁺ and CD16⁺CD57^– NK subsets was observed after the induction. An increase in the T-cell population was also found, with a significant increase in CD3⁺HLA-DR⁺, CD8⁺Leu8^–, and CD4⁺Leu8^– cells. Significant increases in NK activity, from the original level of 32.0±13.7 to 49.9±15.2%, and LAK activity, from 4.8±3.5 to 11.0±6.1%, at Day 7 were observed. Both activities were maintained at high levels during the cytokine injections, but greater enhancement of the killing activities could not be obtained subsequently. When NK and LAK activities were investigated in each subpopulation of CD3^– and CD16^– cells, no remarkable cytotoxic activity could be observed before induction in any subset without NK activity in CD3^– cells (31.1±14.3%). At Day 7, NK activity of CD16^– cells increased up to 21.4±14.9%, accompanied by an increase in CD3^–-cell activity (54.5±20.6%). LAK activities of both subsets were also enhanced, with activity at Day 7 of 6.5±5.6 and 9.4±6.6% in CD16^– and CD3^– cells, respectively. These increased activities were maintained at the same level during the induction. Phorbol myristate acetate-induced polymorphonuclear leukocyte (PMNL) O ₂ ^– generation was significantly increased, from the original 81.1±28.1 to 95.6±34.9 pmol/min/10⁴ cells, after 1 week of treatment. Protein kinase C activity in the cytosol decreased, and the activity in the membrane fraction conversely increased. No remarkable adverse effects except for mild fever were observed. Together with LAK induction ability and PMNL enhancement, with scarce toxicity, a combination of low-dose rIL-2 and rIFN- is thought to be useful in cancer treatments.     

Immunomodulation by indoleamines: Serotonin and melatonin action on DNA and interferon-γ synthesis by human peripheral blood mononuclear cells

Different concentrations of indoleamines, serotonin and melatonin, inhibited phytohemagglutinin stimulated DNA synthesis. Thus, 10^–3 to 10^–4 M of either indoleamine acted at the optimal phytohemagglutinin concentration, while 10^–3 to 10^–7 M acted at suboptimal phytohemagglutinin levels. The serotonin effect was reversed by the serotonergic S₁-S₂ receptor antagonist methysergide but not by the S₂ antagonist ketanserin. This indicates that only the S₁ receptor is involved in the inhibitory effect. Inhibition of lymphoproliferation by indoleamines was also exerted on pokeweed mitogen and protein A fromStaphylococcus aureus stimulations. Serotonin and melatonin also inhibited phytohemagglutinin and protein A from Staphylococcus aureus induction of interferon- synthesis. The initial uptake of Ca²⁺ was not affected by indoleamines, suggesting that it is not the mechanism of their inhibitory effects. As interferon- induced tryptophan uptake by T lymphocyte- and macrophage-depleted populations, and tryptophan is the metabolic precursor of serotonin and melatonin, a new immunoregulatory circuit is postulated.     

Characteristics of human neutrophils obtained by the “skin window” chamber method

The viability, morphological composition, and functional state of human cells migrating into a skin window chamber were studied. After 18–20 h the chamber contained (42.0±5.3) ·10⁶ viable cells/cm² with a high proportion of mature neutrophils (98.6±0.6%). Normal reactivity of the neutrophils of the cell exudate was established by the nitro-BT reduction test. The chamber variant of the skin window method is recommended as a technically simple and physiological procedure for obtaining a pure population of human neutrophils.Department of Bacterial Allergy, Research Institute of Epidemiology and Microbiology, Kazan'. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 11, pp. 623–624, November, 1979.