Vol. 47, No. 1, 1999
CONTENTS
Review
The Immunological Basis of Current and Novel Therapies of Multiple Sclerosis
BENEDICTE DUBOIS and GHISLAIN OPDENAKKER
Abstract. The etiology and the pathogenesis of multiple sclerosis are not yet known. There might be a role for genetic susceptibility, for environmental factors and for inflammatory and immunological changes. Most of the actual therapies are based on the latter two phenomena. We review here corticosteroids, interferon ß and copolymer 1 as the current drugs of choice and compare schematically the immunological basis of the mechanisms of action of these three substances with those of experimental or other treatments.
Keywords: multiple sclerosis; therapy; immunological network; interferon ß; copolymer 1; corticosteroids.
Full-textPDF downloadSuperantigens and Their Role in Autoimmune Disorders
JOEL SCHIFFENBAUER
Abstract. The ability of superantigens to activate large numbers of T cells suggests that they may play a role in the course of autoimmune disorders Data from several animal models of autoimmune disorders including experimental allergic encephalomyelitis and collagen induced arthiritis supports this hypothesis. Administration of bacterial superantigens can induce an exacerbation of the autoimmune process in these models, or induce disease de novo in the appropriately immunized animal. Studies of several human disorders including rheumatoid arthiritis, Kawasaki disease, insulin-dependent diabetes, and psoriasis lend credence to the concept that bacterial superantigens may play a role in the pathogenesis of these diseases. Nevertheless, in some cases, depending on the timing of administration and the model, superantigens may lead to an amelioratiom of the autorimmune process. Based on these results in seems logical to conclude that superantigens can have a significant impact on the course of the immune and autoimmune mediated disorders.
Keywords: superantigen; staphylococcal enterotoxin; autoimmune; experimental allergic, encephalomyelitis.elitis.
Full-textPDF downloadKoch’s Postulates and Autoimmunity: an Opposing Viewpoint
CHAIM PUTTERMAN and YAAKOV NAPARSTEK
Abstract. Autoimmunity is characterized as a state of abnormal specific humoral and cell-mediated responses against constituents of body tissues. One time- honored approach to explaining the pathogenesis of autoimmunity has been application of the Koch’s postulates, on loan from the field of microbiology suggesting that autoantibodies and/or autoreactive T cells are the presumed “ pathogens” of autoimmunity, and that passive transfer of these autoimmune factors to susceptible animals will result in the induction of the autoimmune disease. We suggest that autoimmunity is not in many cases due to the presence of factors leading to the autoimmune response in those susceptible. Instead, it is the lack of a factor which leads to the development of autoimmunity, a factor (cytokine, protein, gene, etc.) which is present in the healthy individual and normally protects in from disordered immune regulation. We propose to direct more research into therapeutic modulation of autoimmunity by administration of putative “protective factors”, rather than by attempts to depress or remove autoreactive cells and antibodies from the autoimmune.
Keywords: autoimmunity; autoantibodies; autoreactive cells; pathogenesis.enesis.
Full-textPDF downloadGene Therapy for Autoimmune Demyelinating Disease of the Central Nervous System
PETER M. MATHISEN and VINCENT K. TUOHY
Abstract. Gene therapy is currently being explored as a new therapeutic treatment of autoimmune disease. The genetic modification of autoreactive memory T cells ( T cell- mediated gene therapy) and autoimmune target tissue ( target tissue gene therapy) to produce immunoregulatory cytokines offers a promising way to regulate autoimmunity. Furthermore, regenerative gene therapy offers the possibility of delivering growth factors to damaged autoimmune target tissue as a way of mediating repair. In the current review we discuss the different experimental models that are being used to test the efficacy of gene therapy in that treatment of autoimmune disease. We also discuss the importance of regulating transgene expression to ensure the therapeutic transgene products are delivered specifically to the autoimmune milieu in an antigen- inducible, non-constitutive manner.
Keywords: gene therapy; autoimmune disease; myelin; inerleukin 10; interleukin 4; cytokines; growth factors.actors.
Full-textPDF downloadVarious
Decrease of Enhanced Interferon a Levels in Sera of HIV-Infected and AIDS Patiens Receiving Combined Antiretroviral Therapy
EGBERT PIASECKI, BRYGIDA KNYSZ, JACEK GĄSIOROWSKI and ANDRZEJ GŁADYSZ
Abstract. In the advanced stages of human immunodeficiency virus (HIV) infection the defective interferon (IFN) responses have been observed. Persisting high lebels of the acid-labile interferons (al-IFNs) have been found in sera of the patients with AIDS. The combined antiretroviral therapy, that included the reverse transcriptase and viral protease inhibitors, resulted in a significant improvement of the clinical state of the majority of HIV-infected patients. In this report we describe the levels of IFNs in 41 HIV patients subjected to the combined treatment. High IFN levels (median 84, up to 576 U/ml) were found in sera of patients classified as the stage C2 or C3 of AIDS before the treatment. The combined therapy resulted in the decrease of IFN levels (median 7.5, up to 24 U/ml) that approached the levels of IFNs detected in the HIV+, A1-A3 stage patients (median 4, up to 36 U/ml). In contrast, the unsuccessful therapy connected with the worsening of the clinical state and the the decrease of CD4+ cell count had no effect on the IFNs level (median 48, up to 96 U/ml). Thus, the measurements of IFN activity in sera may be useful for monitoring the effects of the antiretroviral combined therapy. In sera of the AIDS patients, subjected to the antiviral bioassays, the mixture of the acid-labile and acid-atable form of IFN-a, with the prevailing al-IFN-a, have been detected.
Keywords: interferon a; acid-labile interferon (al-IFN); al-IFN-a, AIDS, HIV-infected patients, combined antiretroviral therapy.
Full-textPDF downloadIn Vitro Secretion of Interleukin 2 and Expression of IL-2 Receptor in Peripheral Blood Lymphocytes in High Risk of Insulin-Dependent Diabets Mellitus Subjects
ADAM KRĘTOWSKI, JANUSZ MYŚLIWIEC, MAŁGORZATA SZELACHOWSKA, CEZARY BRZOZOWSKI, MIROSŁAWA PIETRUCZUK and IDA KINALSKA
Abstract. Interleukin 2 (IL-2) – a Th1 lymphocyte-derived cytokine is at present considered to play an important role in etiopathogenesis of insulin-dependent diabetes mellitus. In the previous studies increased, decreased and unchanged IL-2 levels in patients with recent onset of insulin-dependent diabetes mellitus (IDDM) were found. These differences could be a result of different metabolic status or/and a different stage of the autoimmune process. The aim of our study was to estimate in vitro secretion of IL-2 and CD25 antigen expression by the peripheral blood T lymphocytes in subjcts at the preclinical stage of IDDM (prediabetes), but still without metabolic disturbances. In 27 first degree relatives of IDDM patients with antibodies against ifferent pancreatic islet cell antigens (ICA, GADA, IAA, IA-2) CD25 antigen expression on peripheral blood lymphocytes T was measured by flow cytometry and IL-2 concentration in supernatants of 48 and 72 h cultures of peripheral whole blood with 10 m g/ml PHA was estimated by ELISA. The control group was comprised of 34 age and sex-matched healthy volunteers. In the studied high risk IDDM subjects the decreased CD25 expression in peripheral CD4+ lymphocytes T and a negative correlation between the percentage of CD25+ cells and islet cell antibodies (ICA) titres was observed. No differences in IL-2 levels in supernatants of 48 h and 72 h blood cultures was found in subjects with single antibody (ICA+) in comparison to healthy controls. A significant increase of IL-2 secretion at 72 h of PHA stimulation was shown in first degree relatives of IDDM patients with a combination of 3 or more antipancreatic-B cell antibodies.There were also a significant negative correlation between glutamic acid decarboxylase antibodies (GADA) titres and IL-2 levels in 72 h of culture. The present study suggests the involvement of IL-2 in the pathogenesis of IDDM. The estimation of CD25 antigen expression in the peripheral blood lymphocytes could be an additional immunological marker of identification of subjects in prediabetes.
Keywords: interleukin 2; CD25 antigen; diabetes mellitus type 1; etiopathogenesis.
Full-textPDF downloadCapability of Adriamycin and Busulfan to Induce Adaptive Response in Vitro
ELŻBIETA L. ANUSZEWSKA and JADWIGA H. KOZIOROWSKA
Abstract. The capability to induce an adaptive response by low doses of busulfan (BS) or adriamycin (ADR) was studied in two kinds of mammalian cells with acquired or inherent resistance to ADR (ME!*/R and V3) cultured in vitro. The results indicate the presence of an adaptive responce to ADR in both kinds of used cells pretreated with a low priming dose of ADR. In the same kind of cells no adaptive response to BS priming with a low dose of this drug was found.
Keywords: adriamycin; busulfan; adaptive response.
Full-textPDF downloadHLA-A, B, C Antigens in Pulmonary Sarcoidosis in Polish Population
ANNA DUBANIEWICZ and ZOFIA SZCZERKOWSKA
Abstract. The aim of this study was to analyze association between HLA class I antigens and sarcoidosis in Poland. HLA-A,B, C antigens in a group of 100 patients suffering from sarcoidosis and in group of 100 healthy blood donors were determined. Histocompability typing was performed by the NIH method using commercially available sera. For statistical analisys c 2 test was used after Yates’ correction. The relative risk was calculated by Woolf’s method. We found that HLA-B8 and -Cw7 prevalence was significantly higher in patients with sarcoidosis than in healhy controls. HLA-B35, -B40, -B40, -Cw2 and -Cw4 antigen expression was significantly lower in pulmonary sarcoidosis than in the tested group of healthy individuals. The highest relative risk of sarcoidosis was connected with HLA-B8 and -Cw7. The results obtained suggest that, in the population suffering from pulmonary sarcoidosis in nothern Poland, as compared with the control group of healthy persons, antigens HLA-B8 and -Cw7 are significantly more frequent. It can be assumed that, the presence of these antigens may be connected with a greater risk of pulmonary sarcoidosis. In the group of patients, as compared with the control population, the occurrnce of antigens HLA_B35, -B40, -Cw2 and -Cw4 is significantly more rare.
Keywords: HLA-A, B, C; pulmonary sarcoidosis.
Full-textPDF downloadEffect Of Granulocyte Colony Stimulating Factor Treatment on ex Vivo Cytokine Production by Blood Cells of Patients after Chemotherapy or Radiotherapy
TERESA KAMIŃSKA, ANNA DMOSZYŃSKA, IWONA HUS, ADAM WALTER CRONECK and MARTYNA KANDEFER-SZERSZEŃ
Abstract. We explored ex vivo alterations in the cytokine release of stimulated blood cells taken from 8 patients with hematological malignancies who, after chemotherapy or radiotherapy developed leukopenia, and were treated for 3-7 days subcutaneously with granulocyte colony stimulating factor (G-CSF), daily, dose of 5 m g/kg of body weight. Blood was also taken from 8 heathy controls not treated with G-CSF and from patients before and 24 h after last dose of G-CSF and ex vivo treated with interferon (IFN) inducers: Newcastle disease virus (NDV), phytohemaagglutinin (PHA), concanavalin A (Con A) and with tumor necrosis factor (TNF) inducer – lipopolysaccharide (LPS). Blood cells of patients before G-CSF treatment exhibited ex vivo a low ability was detected. We conclude that G-CSF treatment for 3-7 days does not only increase the number of white blood cells (WBC) and neutrophilic granulocytes but also modify the host response of patients with hematological malignancies to microbial infections.
Keywords: recombinant human colony stimulating factor; interferons; tumor necrosis factor.
Full-textPDF downloadVol. 47, No. 2, 1999
Review
The Complexities of CD28 and CTLA-4 Signalling: PI3K and Beyond
STEPHEN G. WARD
Abstract. A successful immune response requires a set of non-cognate cell-cell interactions which provide the second „costimulatory” signal to the T cells. The best characterized costimulatory receptor expressed on resting T cells is CD28 which provides poorly-defined cyclosporin-resistant biochemical signal(s) that promote expres- sion of several cytokines/chemokines. Another major effect of CD28 ligation is the promotion of cell survival which is thought to occur via the up-regulation of Bcl-xL expression. SD28 shares its ligands B7.1 and B7.2 with the related CTLA-4, which plays an inhibitory role in T cell activation. Manipulation of CD2B/CTLA-4 interac- tions with their natural ligands has provided exciting results in transplantation and tumor therapy settings and also has potential in the treatment of several diseases such as arthritis and multiple sclerosis, asthma and protection against HIV infection. The biochemical basis for the different functional outcomes of CD2B and CTLA-4 ligation has been the subject of intense investigation over the past few years. This review will focus on our current understanding of the biochemical signals that may be involved in regulating the different functional outcomes of CD2B and CTLA-4, with particular emphasis on the role played by the PI3K-dependent signalling cascade.
Keywords: T cell; CD2B; CTLA-4; PI3K; signalling.alling.
Thymic Peptides and Preparations: an Update
OSCAR J. CORDERO, ALICIA PIŃEIRO and MONTSERRAT NOGUEIRA
Abstract. The possibilities of thymic peptides in human therapy are still being described. Here, we focus on their general characteristics and on recent advances in this area.
Keywords: thymus; thymic peptides; preclinical investigation; therapeutic use; clinical trials.trials.
Tumor Escape from Immune Surveillance
RÉGIS T. COSTELLO, JEAN ALBERT’GASTAUT and DANIEL OLIVE
Abstract. The bases for an efficient anti-tumor immune response begin to be better defined. Nonetheless, neo- plastic cells develop various strategies to escape immune surveillance, which are discussed here in order to better design the therapeutic possibilities of immune manipulation. The absence of specific tumor antigen as well as the weak expression of major histocompatibility complex (MHC) molecules hinder the recognition of the neoplastic cells by T lymphocytes. The defect of expression by the tumor of the ligands for the T cell activation costimu- latory molecules is particularly harmful for the immune response since it induces tolerance. Finally, tumor cells can inactivate effector T lymphocytes through the secretion of inhibitory cytokines, induction of apoptosis or functional inactivation. The multiplicity of the means to oppose an effective anti-tumor response challenges the adaptative mechanisms of the immune system. For example, the natural killer cells target tumor cells not express- ing MHC class I molecules. Numerous possibilities of tumor immunogenicity restoration have been demonstrated at least in vitro, such as stimulation of the cancerous cells by CD4O or cytokine treatment, which could lead to several promising therapeutical approaches.
Keywords: cancer; immunodeficiency; immunotherapy; lymphocyte.hocyte.
Human Acid-Labile Interferon a
EGBERT PIASECKI
Abstract. In acquired immune deficiency syndrome (AIDS) and autoimmune diseases, like systemic lupus erythematosus (SLE), persisting high levels of interferon (IFN) are detectable in plasma. The IFN has been identified as an unusual human acid-labile IFN-a (al-IFN-a). Its properties are similar to that of the known a interferons except sensitivity to acid treatment (pH 2) which is characteristic for IFN-y. The nature of al-IFN-a is not known. Four hypotheses have been presented that suggested that: a) al-IFN-a may be a product of a distinct IFN gene; b) or a posttranscriptionally modified IFN-a molecule; c) the phenomenon of al-IFN-a may be an effect of synergistic action of a mixture of acid-stable IFN-a and acid-labile IFN-y; d) or the effect may be a result of an interaction of acid-stable IFN-a with an unknown factor(s) present in plasma and associated with progression of HIV infection or autoimmune diseases. Neither of the hypotheses have been experimentally proven. To verify the most probable hypothesis of the synergistic interactions between the acid stable and labile IFNs, the experi- ments with the artificial mixtures of nHuIFN-a and rHuIFN-y were performed. The synergistic effect was abolished by the treatment either with pH 2 or with anti-IFN-y antibodies. The residual activity was similar in both cases and corresponded to acid-stable IFN-a. However, al-IFN-y (AIDS serum with high IFN level) was found to be much more sensitive to acid treatment and only negligible effect of anti-IFN-y serum was observed. It suggests that the synergistic effect may be only slightly responsible for the phenomenon of acid lability of IFN-a. Foor explanation of the occurrence of al-IFN-a the hypothesis of existence of a factor(s) interacting with IFN-a should be taken into consideration.
Keywords: interferon; acid-labile interferon a; synergistic action of IFN-a and IFN-y; AIDS; HIV infection; systemic lupus erythematosus; autoimmune diseases.seases.
Substance Abuse and HIV-gp120: Are Opiates Protective?
GEORGE B. STEFANO
Abstract. There has long been a popular conceptual linkage between human immunodeficiency virus (HIV) acquisition and substance abuse involving needles. Indeed, in vitro studies demonstrate that these substances promote the replication of HIV. Included in these in vitro studies is a linkage or association of tissue damage and viral load with the actions HIV envelope protein gp120 with substances of abuse. However, detailed epidemio- logical studies have not supported this association of substance abuse and HIV acquisition, viral load and exacerbated tissue damage. It is with this understanding that we undertake a reevaluation of the in vitro studies within the context of the microvascular immune environment. In this regard, a counter-intuitive hypothesis emerges, namely, that specific substances of abuse may afford a degree of protection from HIV infection. This new hypothesis involves the neural, immune, and vascular signaling molecule nitric oxide.
Keywords: gp120; morphine; monocytes; HIV; immunovascular regulation; nitric oxide. oxide.
Clinical Immunology
Interferon y as Immunomodulator in a Patient with Multiple Myeloma
TERESA KAMIŃSKA, ANNA DMOSZYŃSKA, MARIA CIOCH, IWONA HUS, DARIUSZ JAWNIAK, AGNIESZKA SZUSTER-CIESIELSKA and MARTYNA KANDEFER-SZERSZEŃ
Abstract. We describe here a patient with multiple myeloma, who, while in remission after chemotherapy, received 100 mg of rIFN-’y (Imukin, Boehringer, Ingelheim) subcutaneously 3 times a week for 4 weeks as supportive therapy before autologous peripheral blood stem cell transplantation (PBSCT). The patient was moni- tored for serum IFN, TNF, IL-2 activities and for the ability of peripheral blood leukocytes (PBL) to produce IFN-a/(3, IFN-y, IL-2 and TNF-a after in vitro induction. Changes in the percent of plasma cells in the bone marrow, in the total and differential white blood cell counts, in T cell subsets and NK cells were also monitored. IFN-y yielded no clinical antitumor activity. The number of bone marrow plasma cells increased, however, the percentage of blood and bone marrow NK cells and the CD4/CD8 T cell subset ratio decreased. Monitoring the cytokine production ability of PBL during IFN-’y therapy revealed an increase in IL-2, IFN-’y and TNF-a titers produced upon in vitro induction after 2 weeks of treatment (6 injections of rIFN-y). However, after 9 injections there was a significant decrease in IFN-y and IL-2 production in the PBL, and at the end of therapy ( 12 injections) the decrease not only in IL-2 and in IFN-y but also in IFN-a production was observed. In contrast to these changes, TNF production was strongly enhanced and reached the level observed before the therapy. These data suggest that the schedule of IFN-y therapy in multiple myeloma should perhaps be adapted to become more effective, taking advantage from the immunomodulating activity of IFN-’y.
Keywords: multiple myeloma, rIFN-y therapy; TNF.y; TNF.
Lactoferrin Increases the Output of Neutrophil Precursors and Attenuates the Spontaneous Production of TNF-a and IL-6 by Peripheral Blood Cells
MICHAŁ ZlMECKI, KRYSTYNA SPIEGEL, ANDRZEJ WLASZCZYK, ANDRZEJ KÜBLER and MARIAN L. KRUZEL
Abstract. The aim of this report was to investigate the effects of bovine lactoferrin (BLF) taken orally (per os) by healthy individuals, on selected immune parameters. Three groups of volunteers (7 persons per group) were taken daily for 7 days, one capsule containing 2, 10 or 50 mg of BLF. A control group has taken placebo only. Venous blood was taken for tests a few hours before the first dose of BLF, one day and 14 days after the last dose of the preparation. For the evaluation of BLF action on the immune response system we have chosen 3 parameters: content of neutrophil precursors in the peripheral blood (in percentage), spontaneous production of interleukin 6 (II,-6) and tumor necrosis factor a (TNF-a) by unstimulated blood cell cultures. We found that oral treatment of volunteers with BLF caused a transient (one day after last dose) increase of immature forms of neutrophils in the circulating blood. That increase was more than 2-fold in the case of 10 mg dose. However, statistically significant increases in the percentage of neutrophil precursors were also registered at doses of 2 and 50 mg of BLF. No change in the immature cell content was observed in the placebo group. The treatment with BLF also resulted in a profound decrease of the spontaneous production of IL-6 and TNF-a by cultures of peripheral blood cells. This decrease was significant ( 10 mg/dose) one day following the last dose of BLF and persisted for additional 14 days. These results confirmed our earlier data on the effects of per os treatment with a nutritional preparation containing BLF. Furthermore, we were able to closer establish the optimal dose of BLF affecting selected immune indices.
Keywords: bovine lactoferrin; blood cells; neutrophil precursors; interleukin 6; tumor necrosis factor a.ctor a.
Hydrogen Peroxide in Expired Air Condensate Correlates Positively with Early Steps of Peripheral Neutrophil Activation in Asthmatic Patients
ADAM ANTCZAK, DARIUSZ NOWAK, PIOTR BIALASIEWICZ and MAREK KASIELSKI
Abstract. We have found an increased H202 level in expired air of asthmatic patients. Neutrophils from these subjects generated higher amounts of superoxide radicals after challenge with phorbol esters than those from healthy subjects which may result from an increased activity of NADPH-oxidase. The enhanced Ca2+ mobilisation in neutrophils from asthmatics could be responsible for increased production and subsequent elevated H2O2 concentration in expired breath condensate. In this study we wished to determine whether neutrophils of asthmatic patients have enhanced [Ca ]i response after N-formyl-methionyl-leucyl-phenylalanine – fMLP challenge as compared with cells from healthy donors, and if so, does it correlate with H202 levels in expired air. We examined ? 1 patients, 10 healthy individuals as a control group (mean age 34.3 ± 5.5, 6 males and 4 females) and 11asthmatic subjects (mean age 38.2 ± 7.2, 7 males and 4 females). The rise of [Ca2+]i as an early event of neutrophil activation, was measured spectrofluorimetically with Fura-2-AM. The mean H202 level, measured spectrofluorimetrically in the expired breath of asthmatics, was 20-fold higher than that in healthy control (0.18 ± 0.20 vs. O.OI ± 0.04 pM, p<0.05). [Ca2+]i increase after challenge by fMLP (0[Ca2+]i) was much higher in asthmatics than in control group (205.0 ± 44 vs. 113.0 ± 22 nM, p<0.05, respectively). A strong correlation was observed between H202 and [Ca2+]i and maximal velocity of increase in [Ca2+]i in asthmatics (r = 0.87, p<0.01 and r = 0.64, p<0.05). We conclude that elevated H202 level in the expired breath condensate of asthmatics can be generated by activated neutrophils in the course of mucosal inflammation observed in bronchial asthma.
Keywords: bronchial asthma; hydrogen peroxide in breath condensate; neutrophils; intracellular calcium.alcium.
Vol. 47, No. 3, 1999
Review
Involvement of Fas/FasL System in the Pathogenesis of Autoimmune Diseases and Wilson’s Disease
GIORGIO STASSI, VALENTINA DI FELICE, MATILDE TODARO, FRANCESCO CAPPELLO, GIOVANNI ZUMMO, FELICIA FARINA, MASSIMO TRUCCO and RUGGERO DE MARIA
Abstract. The interaction of Fas with FasL has been demonstrated to be implicated in the pathogenesis of several autoimmune and liver diseases. Recently, attention has been focused on the hypothesis that thyrocytes and b cells undergo massive Fas/FasL?mediated apoptosis during autoimmune response. Similarly, hepatocyte cell death occurring following copper accumulation points towards the same mechanism.
Keywords: autoimmune diseases; apoptosis; Fas; Hashimoto’s thyroiditis; Wilson’s disease; insulin?dependent diabetes mellitus.
Virokines: Mediators of Virus?Host Interaction and Future Immunomodulators in Medicine
GIRISH J. KOTWAL
Abstract. A decade ago, after the discovery of the major secretory protein of vaccinia virus with structural similarity to complement control, the term virokine was coined. The term virokine, simply refers to a virally encoded secretory protein. During the past decade several virokines were discovered and most of them have been found to have immunomodulatory effects. A subset of virokines which resemble cytokine/chemokine receptors have been termed viroceptors. Examples of viroceptors include the TNF receptor homolog and the IL?1b receptor homolog. During the past several years animal models have been developed to try to understand the in vivo role of the virokines. It has become evident from at least two studies that quite a few of the virokines down?regulate the inflammatory response elicited during infection. This down?regulation at least in one model system seems to indicate that it ensures the preservation of the viral habitat (site of infection). One obvious spinoff of the research on virokines is a new class of immunomodulators has become available as therapeutics in alleviating the symptoms of inflammatory disease conditions.
Keywords: virokines; viroceptors; virus?host interaction; virokine therapeutics.
How Does the Major Histocompatibility Complex Influence Behavior?
EDELGARD JANSSEN and NICHOLAS ZAVAZAVA
Abstract. The major histocompatibility complex (MHC) encodes highly polymorphic cell surface glycoproteins that form the basis of immunological individuality. It has been postulated that MHC besides its role in immune defence also determines behavior through formation of specific odor cues. In addition several studies have implicated MHC disassortative odor and mating preferences in mice, rats, and humans. Further leading studies have suggested that mice and humans prefer to mate with MHC dissimilar individuals. Although the latter remains controversial, MHC dependent mating preferences provide a potentially important selective factor driving the polymorphisms of the MHC genes. Here we review some of the available data and hypotheses on the influence of the MHC on behavior and discuss its molecular and chemical basis.
Keywords: major histocompatibility complex; human leukocyte antigen; odor; individual chemosignals; perception; mate choice.
Cyclolinopeptides and Their Analogs – a New Family of Peptide Immunosuppressants Affecting the Calcineurin System
IGNACY Z. SIEMION, MAREK CEBRAT and ZBIGNIEW WIECZOREK
Abstract. The results of the investigation of immunosuppressive activity of cyclolinopeptide A (CLA – cyclic hydrophobic nonapeptide present in the linseeds) and its analogs are discussed. The results obtained for other natural cyclic peptides showing structural similarities with CLA (antamanide, cycloamanides, hymenistatin, hymenamides) are also reviewed. It results from these investigations that the molecular mechanism of the CLA action is the same as that of cyclosporin A and FK?506 compound, i. e. it consists in formation of the complex with cyclophilin and inhibition – in this form – of the phosphatase activity of calcineurin. The results also suggest that the immunosuppressive activity of these compounds resides in their –Pro?Xxx?Phe? fragment, where Xxx is a hydrophobic (e. g. Leu, Val) or aromatic amino acid residue.
Keywords: antamanide; cycloamanides; cyclolinopeptide A; hymenamides, hymenistatin; peptide immunosuppressants
Experimental and Clinical Immunology
Nitric Oxide, Heparin and Procaine Treatment in Experimental Ceruleine?Induced Acute Pancreatitis in Rats
MAREK DOBOSZ, ZDZISŁAW WAJDA, STANISŁAW HAĆ, JOLANTA MYŚLIWSKA, EWA BRYL, LUCJANNA MIONSKOWSKA, ANDRZEJ ROSZKIEWICZ and ANDRZEJ MYŚLIWSKI
Abstract. The aim of the study was to investigate the impact of L?arginine (nitric oxide donor), L?NNA (NO synthase inhibitor), heparin and procaine on the pancreas’ microcirculation, serum interleukin 6 (IL?6) level, and microscopic alterations of the pancreatic gland in acute pancreatitis (AP) in rats. AP was induced by 4 i. p. injections of cerulein (15 mg/kg/h). Microcirculatory values of the pancreas were measured by means of laser Doppler flowmetry 5 h after the first cerulein injection. Remarkable morphologic changes in the pancreas, including parenchymal necrosis, an elevation of serum IL?6 activity, and significant drop of pancreatic capillary perfusion was observed in rats with NO synthase inhibition. L?arginine improved the pancreatic microcirculation but worsened the microscopic alterations within the pancreas. Heparin had a beneficial effect on the microcirculatory values, serum IL?6 activity, and morphologic changes. Procaine had no effect on the course of AP. Authors conclude that heparin, improving the pancreatic capillary blood perfusion, may be considered as a promising therapeutic agent in acute pancreatitis.
Keywords: acute pancreatitis; microcirculation; interleukin 6; nitric oxide; heparin; procaine.
Tumor Infiltrating Lymphocytes in HLA+ and HLA– Laryngeal Cancer – Quantitative Approach
GRZEGORZ DWORACKI, ALEKSANDRA KRUK?ZAGAJEWSKA, ELŻBIETA JEŻEWSKA, JAN SIKORA1 and JAN ŻEROMSKI
Abstract. In search of factors governing the accumulation of tumor infiltrating lymphocytes (TIL), frozen sections from fresh surgical specimens of laryngeal carcinoma (n=36) were tested by alkaline phosphatase–anti?alkaline phosphatase (APAAP) immunohistochemistry for monomorphic determinants of HLA class I and class II expression on tumor cells and for the distribution of lymphoid cells bearing CD differentiation antigens. Cell subsets were quantitated in two tumor compartments, tumor mass and tumor stroma, by computer?assisted image analysis. In a portion of examined samples lymphoid cell suspension was isolated from cancerous tissues and assessed by flow cytometry. It has been found that T cells, localized mostly in tumor stroma, were predominant cell population in the tumor microenvironment. Their ability to penetrate tumor mass but not tumor stroma, by CD8+ T cells in particular, but also by natural killer (NK) cells, was associated with HLA class I antigen expression on tumor cells. In flow cytometric analysis activated T lymphocytes (CD3+DR+) were abundant in HLA+ tumors as compared to HLA– ones. In 4 year follow up of 20 patients the mortality was higher in HLA– group but the data were not statistically significant. These results show that HLA class I expression on tumor cells favor penetration of cytotoxic lymphoid cells into tumor mass, at least in the laryngeal cancer.
Keywords: laryngeal carcinoma; HLA antigens; tumor infiltrating lymphocytes; APAAP reaction, image analysis; flow cytometry.
Adhesion Molecule Expression Stimulated by Bacteroides thetaiotaomicron Cell?Surface Antigens
ALICJA ROKOSZ, FELICJA MEISEL-MIKOŁAJCZYK, CEZARY MALCHAR, MARIA NOWACZYK and ANDRZEJ GÓRSKI
Abstract. Bacteroides thetaiotaomicron, a Gram?negative anaerobic rod belonging to the Bacteroides fragilis group (BFG), is involved in many systemic and local, most frequently suppurative infections in man. The cell envelope of these rods is composed of two carbohydrate?containing antigens: lipopolysaccharide (LPS) and capsular polysaccharide (CPS). Adhesion molecules ICAM?1, VCAM?1 and E?selectin (ELAM?1) are induced on the endothelial cells by mediators of inflammation. The aim of this study was to assay the ability of B. thetaiotaomicron surface antigens to induce adhesion molecule expression on the endothelial cells. The influence of LPS and CPS on the expression of adhesion molecules on HMEC?1 cell line was examined in an ELISA test. ELISA was performed with monoclonal mouse anti?human: ICAM?1, VCAM?1 and E?selectin antibodies of the IgG class. B. thetaiotaomicron lipopolysaccharides revealed the ability to induce ICAM?1, VCAM?1 and E?selectin expression on the endothelial cells. Their activities were similar, but lower than the activity of Eschericha coli LPS. ICAM?1 was the most stimulated adhesion molecule. The strongest activation by LPS was achieved at the concentrations of 10. 0 and 1. 0 mg/ml. The ability of capsular polysaccharide to induce the expression of adhesion molecules was considerably weaker.
Keywords: adhesion molecules; endothelium; Bacteroides thetaiotaomicron; lipopolysaccharide; capsular polysaccharide
Various
Isolation of Human Lutropin from Woman Urine and Comparison of Its Properties with Pituitary Hormone
EWA KUROWSKA and APOLINARY SZEWCZUK
Abstract. Lutropin was isolated from woman preovulatory urine by immunoaffinity chromatography using a column with monoclonal antibody (mAb) anti?bhLH(37) coupled to Sepharose CL 4B. As it was demonstrated the isolated hormone, as well as pituitary lutropin, were separated in SDS?PAGE into several well visible fractions with 30–94 kDa molecular mass and scarcely visible fractions with 14–20 kDa. All fractions reacted only with mAb anti?ahCG(99) ?HRP but not with mAb anti?bhLH?HRP. Pretreatment of pituitary lutropin with PN?Gase F did not affect its electrophoretic pattern. After boiling the hormone with SDS and bME no fractions in SDS?PAGE were observed. No substantial differences in affinity chromatography on Con A?Sepharose between pituitary and urinary lutropin were noted. Some differences between these two hormone preparations were observed in assays performed with several ELISA variants. Using two pairs of mAbs anti?bhLH for ELISA technique no hormone was assayed in urine samples from women, collected between 12 and 16 days of menstrual cycles.
Keywords: human lutropin; human luteinizing hormone; urine lutropin; pituitary lutropin; affinity chromatography; SDS?PAGE; comparative assays.
Antifungal Activity of 2-(4-Chlorophenyl)-1,2-Benzisoselenazol-3(2H)-One, the Analog of Ebselen
MAŁGORZATA BIEŃ, BARBARA BŁASZCZYK, KATARZYNA KALINOWSKA, JACEK MŁOCHOWSKI and ANNA D. INGLOT
Abstract. The antimicrobial activity of 8 selenoorganic compounds (3-benzisoselenazoles, 1-benzisoselenazolone oxide and 4-disaryl diselenides) was investigated. It was found that selenoorganic compounds from benzisoselenazolone group suppress growth of some fungi and bacteria. The growth of Saccharomyces cerevisiae S127-8b and Candida albicans 258 strains was strongly inhibited by the 2-(4-chlorophenyl)-1, 2-benzisoselenazol-3(2H)-one. Also Ebselen and 2-acetyl-1, 2-benzisoselenazol-3(2H)-one caused strong inhibition of Saccharomyces cerevisiae S127-8b growth but a lower effect was observed in assays with Candida sp. strains. Benzisoselenazolones were also found to have antibacterial activities. They significantly reduced the growth of Gram-negative Escherichia coli K-12 ROW and Gram-positive Staphylococcus aureus 209P (Oxford) bacteria strains.
Keywords: selenoorganic compounds; Saccharomyces cerevisiae; Candida albicans; Staphylococcus aureus; Escherichia coli.
Investigation of Influence of Proteus mirabilis LPS Polysaccharide Part on the Murine Immune Cells Activation
MAGDALENA KLINK, CHUNG HEE SONN, WIESŁAW KACA and YOUNG SANG KIM
Abstract. The biological activities were investigated of Proteus mirabilis lipopolysaccharides (LPSs) and their fragments, namely, the induction of nitric oxide (NO) and interleukin 1 (IL?1) synthesis by murine macrophages and the proliferation of murine spleen cells. The O?specific polysaccharide (F1), core oligosaccharide (F2) and lipid A were as effective as intact LPS in stimulating murine macrophages to produce NO. IL?1 synthesis was also induced by all studied types of endotoxins (S, Ra, Re) and partial structures, however F1, F2 and lipid A fractions required the presence of serum. In contrast to LPS, the O?specific polysaccharide, core oligosaccharide and lipid A were not able to induce the blast response of murine non?adherent splenocytes.
Keywords: Proteus mirabilis; lipopolysaccharide; nitric oxide; interleukin 1.
Vol. 47, No. 4, 1999
Review
Mechanisms of Immune Regulation in Alzheimer’s Disease: a Viewpoint
FLORENTINE MARX, IMRICH BLASKO and BEATRIX GRUBECK-LOEBENSTEIN
Abstract. The immune system may play an important role in the neurodegenerative process in Alzheimer’s disease (AD). Complement components, eicosanoids and cytokines are found in cerebral amyloid plaques. These inflammatory proteins may stimulate the amyloid b (Ab) production, support its aggregation and increase its cytotoxicity, thus aggrevating the pathology of AD. Ab may trigger their release from activated microglia and astrocytes which are the main sources of these proteins. However, there are also indications for a protective role of the immune system against the development of AD. Microglial cells have been shown to degrade Ab and recent evidence suggests a role of autoreactive Ab?specific T cells in the elimination of the peptide. This mechanism seems to be impaired in the majority of patients with AD. An Ab?specific immune reaction may thus represent a natural defence mechanism directed against the accumulation of dangerous amyloidogenic substances. Impairment of the immune system and the failure to eliminate a toxic metabolite can be the basis for a chronic non?specific inflammatory process in the brain, as described above. AD is a good example how an immune response may lead to tissue destruction and neuronal loss instead of maintaining the integrity of the body.
Keywords: Alzheimer’s disease; Alzheimer amyloid precursor protein; amyloid b; cytokines; T lymphocytes; autoreactivity; inflammation.
Mechanistic and Clinical Aspects of b?Lactam Antibiotics and b?Lactamases
LAKSHMI P. KOTRA and SHAHRIAR MOBASHERY
Abstract. Bacterial infections have been a major cause of concern in the recent years due to the emergence of drug resistance strains and inability of the current therapeutic regimens to treat these infections in certain cases. b?Lactam antibiotics have been drugs of choice since the introduction of penicillin. These drugs inhibit bacterial cell?wall?synthesizing enzymes, the so?called penicillin?binding proteins (PBPs) selectively, thus providing an effective strategy for treatment of the bacterial infections. Significantly, bacteria have developed resistance mechanisms to neutralize the antibiotic action of b?lactam drugs. b?Lactamases are enzymes that hydrolyze the b?lactam moiety of these drugs, rendering them inactive. This is the primary mechanism of resistance to this class of antibiotics. There are 255 known b?lactamases to date and the continued use of b?lactams may select for newer variants yet. A discussion of the roles of these enzymes in the manifestation of the drug?resistant phenotype and their implications for pathogenecity of clinical strains of bacteria is presented.
Keywords: b-lactams; b-lactamases; antibiotic; drug resistance; bacterial infection.
Expression and Function of CD30 on T Lymphocytes
MACIEJ TARKOWSKI
Abstract. T cell receptor, accessory molecules, cytokines are important regulatory factors that determine the development and function of T lymphocytes. Among them are also molecules belonging to superfamily of tumor necrosis factor receptor (TNFR) which beside CD30 include CD27, CD40, TNFR?I and ?II, Fas (CD95), OX40, 4?1BB (CDw137), nerve growth factor receptor, lymphotoxin?b receptor, Apo3/DR3/Ws1?1/lymphocyte associated receptor of death, DR4, DR5/TNF?related apoptosis?inducing ligand, osteoprotegerin, and TNFR?related 2. CD30 recognized originally on Reed?Sternberg cells of Hodgkin’s lymphoma became of interest in studies of Th1 and Th2 cell differentiation. This paper shows recent findings regarding CD30 expression and its pleiotropic role in T cell function. It provides information about controversial role of CD30 as Th2 cell differentiation marker and gives concise insight into the function of this receptor as a signal transducing molecule.
Keywords: CD30; T cells; cytokines.
Immunotherapy with Recombinant Human Interleukin 2 in Patients with Hematological Malignancies after Bone Marrow or Peripheral Blood Stem Cell Transplantation
IRENA FRYDECKA, AGATA KOSMACZEWSKA, DOROTA BOĆKO, LIDIA CISZAK2 and PAWEŁ KACZMAREK
Abstract. High-dose chemotherapy in conjunction with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) is increasingly being used for treatment of patients with hematological malignancies. Residual tumor cells, resistant to high?dose chemoradiotherapy, are responsible for reccurence of the disease. Interleukin 2 (IL?2), a pleiotropic cytokine which plays a central role in immune response, has been introduced in several clinical trials in patients with hematological malignancies after BMT or PBSCT to increase immunocompetence of these patients and eradicate residual malignant cells. At present there is no general agreement on the optimum dosage or route of administration and clinical trials also gave conflicting results. Establishment of optimum dosage schedules and methods of administration should enable a better assessment of the place of IL?2 in the treatment of these patients.
Keywords: interleukin 2; bone marrow transplantation; peripheral blood stem cell transplantation.
Clinical Immunology
Serum Haptoglobin, CA 125 and Interleukin 6 Levels in Malignant and Non?Malignant Tumors of the Ovary
WANDA DOBRYSZYCKA, IWONA KĄTNIK?PRASTOWSKA, JERZY GERBER, KRYSTYNA LEMAŃSKA, KRYSTYNA UTKO and KRZYSZTOF ROZDOLSKI
Abstract. In sera of women with malignant and non?malignant ovarian tumors, concentrations of the following proteins were determined: haptoglobin, measured by the reactions either with hemoglobin (Hp?Hb) or with concanavalin A (Hp?Con A), CA 125 antigen and interleukin 6 (IL?6). Besides preoperative data, obtained from all the patients and the group of healthy women, in the patients with ovarian cancer (III/IV FIGO stages) effects of administration of cytostatics were measured by monitoring changes in the levels of the examined parameters through the course of the therapy. All the results were submitted to statistical evaluation which showed differences and correlations among definite groups (normal/non?malignant, normal/cancers, non?malignant/cancers). Similar results were obtained for Hp?Hb and CA 125 determination. Moreover, a correlation between haptoglobin level and age was found. Patterns of monitoring revealed a surprising absence of Hp?Con A interaction in some cases.
Keywords: haptoglobin?hemoglobin; haptoglobin?concanavalin A; interleukin 6; CA 125; ovarian cancer.
Development and Disappearance of Tolerance to Induction of Interferon and Tumor Necrosis Factor Response in Athletes Treated with Natural Immunostimulant
ANNA D. INGLOT, KRZYSZTOF A. SOBIECH, JANINA ZIELIŃSKA?JENCZYLIK, ALICJA SYPUŁA, JACEK MAJDA3 and MARIA LORENC1
Abstract. The effect of nonspecific immunostimulation was examined in 15 basketball players subjected to extensive physical effort. The Tołpa* Torf Preparation (TTP*), a natural immunostimulating drug, was applied orally, one 5 mg tablet daily, in two 21?day cycles, separated by 2?week hiatus. Blood samples were collected 4 times, after each of two TTP* cycles and after the first and second hiatus. Whole blood assay was used to determine the spontaneous and induced production of interferon (IFN) and tumor necrosis factor (TNF). The levels of the cytokines were measured by microbioassays. TTP* stimulated synthesis of IFN and TNF in the whole blood cultures. However, after the oral administraton of TTP* for 3 weeks the leukocytes of the athletes developed hyporeactivity to IFN induction by TTP* and to a lesser extent to another “superinducer” – a mixture of phytohemagglutinin and bacterial lipopolysaccharide. The hyporeactivity state disappeared spontaneously within 2 weeks. In contrast, the tolerance to TNF induction did not develop during the TTP* administration. The increase of immunoglobulins, mainly of IgM and IgG classes and an acute phase protein – a1?antitrypsin, was observed at the late phase of the treatment. We suggest that the cytokine levels may be early markers for immunoprophylaxis. Furthermore, high production of IFN and TNF may be associated with extensive physical effort.
Keywords: nonspecific immunostimulation; basketball players; interferon; tumor necrosis factor; whole blood assay.
Heparin Modulates Migration of Human Peripheral Blood Mononuclear Cells and Neutrophils
TERESA ŻAK-NEJMARK, MARYLA KRASNOWSKA, RENATA JANKOWSKA2 and MAREK JUTEL1
Abstract. Evidence has now accumulated that heparin can significantly affect immune response including allergic inflammation. Cell motility is supposed to be very crucial in this process. Thus the aim of our study was to investigate whether heparin is a chemoattractant for some inflammatory cells and is also capable of influencing chemotaxis induced by typical chemoattractants. Peripheral blood mononuclear cells (PBMCs) and neutrophils from 10 healthy subjects were obtained by gradient centrifugation. Chemotaxis assays towards either heparin (molecular weight 16 kDa) or low molecular weight heparin – fraxiparine (molecular weight 5 kDa) were performed in Boyden chambers. We found that both heparin molecules are chemoattractants for both PBMCs and neutrophils in the wide concentration range (0.1–2000 mg/ml). However, maximal chemotaxis was observed at concentrations 50–100 mg/ml (fraxiparine) and 1–50 mg/ml (heparin). We also found that fraxiparine was able to significantly increase chemokinesis and decrease chemotaxis in the gradient of both fMLP and IL?8. These results indicate that heparin is a potent regulator of cell migration.
Keywords: peripheral blood mononuclear cells; neutrophils; migration; heparin influence.
Soluble CD23 in Allergic Diseases
BARBARA ROGALA and BARBARA RYMARCZYK
Abstract. CD23, a differentiation marker of B cells is identified with the low?affinity receptor for IgE – FceRII. The CD23 molecule is continuously cleaved by autoproteolysis into soluble fragments called sCD23, considered as a multifunctional cytokine. sCD23 is supposed to play an important role in IgE synthesis. IgE is a hallmark of atopy and its overproduction is a characteristic feature of allergic diseases. The aim of this study was to determine sCD23 (25 kDA) serum levels in patients with inhalant allergy and hymenoptera venom?induced allergy with relevance to IgE system. The trial consisted of 18 patients with pollinosis, 25 with house dust mite allergy and 12 with hymenoptera venom?induced allergy. Eighteen healthy volunteers without signs of atopy served as a control group. Serum levels of sCD23 (25 kDa), total IgE and allergen specific IgE were measured as well. The results were presented as median value, 25–75% range and a total value range. Nonparametric tests (the U Mann?Whitney test, Kruskal and Wallis test and Spearman’s correlation rang test) were used. In patients with allergic disorders serum levels of sCD23 were significantly higher than in the control group (p<<0. 05). No correlation between IgE levels and sCD23 was detected in all the investigated groups. sCD23 does not appear to be a hallmark of allergic diseases, however serum level of that molecule is significantly elevated in patients suffering from allergic disorders. No correlation between sCD23 and IgE has been observed. sCD23 serum level has no relevance to the types of allergic diseases.
Keywords: soluble CD23; allergy.
Regulatory Effects of Lactoferrin and Lipopolysaccharide on LFA?1 Expression on Human Peripheral Blood Mononuclear Cells
MICHAŁ ZIMECKI, RYSZARD MIĘDZYBRODZKI, JOEL MAZURIER and GENEVIĚVE SPIK
Abstract. The aim of this study was to investigate effects of human lactoferrin (hLF) with regard to LFA?1 expression on unstimulated and lipopolysaccharide (LPS) ?activated human peripheral blood mononuclear cells (PBMC). The investigations were carried out on 30 healthy volunteers, males and females, 24–58 years old. We found that hLF, at an optimal dose of 5 mg/ml/106 cells in 24?hour culture, exerted regulatory effects on LFA?1 expression, depending on distribution of this molecule on cells in control cultures and on the effects of LPS. First, we revealed several patterns of LFA?1 distribution and density of this marker among studied individuals. The effects of LPS and hLF on LFA?1 expression patterns were differential. LFA?1 expression was stimulated by individual actions of LPS or hLF, additive or synergistic effects of both factors, it could be also inhibited by hLF alone or in combination with LPS. In about one third of cases no significant effects of LPS or hLF on LFA?1 expression were seen. Removal of monocytes from the PBMC population diminished LFA?1 expression in control cultures and abolished LPS? or hLF?elicited changes. The regulatory effects of hLF were also blocked by treatment of PBMC cultures with anti?tumor necrosis factor alpha (TNF?a) antibodies. Taken together, the data showed that hLF and LPS had immunoregulatory properties with respect to LFA?1 expression on human PBMC and that these actions were mediated by monocytes and TNF?a.
Keywords: lactoferrin; lipopolysaccharide; LFA?1 (CD11a); peripheral blood mononuclear cells; regulation.
Vol. 47, No. 5, 1999
Review
Phage Therapy: Past History and Future Prospects
RICHARD M. CARLTON
Abstract. Bacterial viruses (bacteriophages, also called “phages”) can be robust antibacterial agents in vitro. However, their use as therapeutic agents, during a number of trials from the1920s to the 1950s, was greatly handicapped by a number of factors. In part, there were certain limitations inherent in phage physiology (e. g. narrow host range, and rapid clearance from the body); in part there were technological limitations in the era (e. g. lysogeny not yet discovered); but the greatest limitation was the highly inadequate scientific methodologies used by practitioners at the time (e. g., their failure to conduct placebo?controlled studies, to remove endotoxins from the preparations, and to re?confirm phage viability after adding sterilizing agents to the preparations). In recent years, well?controlled animal models have demonstrated that phages can rescue animals from a variety of fatal infections, while non?controlled clinical reports published in Eastern Europe have shown that phages can be effective in treating drug?resistant infections in humans. This encouraging data, combined with the fact that drug?resistant bacteria have become a global crisis, have created a window of opportunity for phage therapy to be tested anew, this time using modern technologies and placebo?controlled designs. If successful, it can be used as a stand?alone therapy when bacteria are fully resistant to antibiotics, and as a valuable adjunct to antibiotics when the bacteria are still susceptible.
Keywords: bacteriophage; phage; bacterial viruses; bacterial infections; multidrug resistance.
Biochemical and Immunological Characteristics of 4?1BB (CD137) Receptor and Ligand and Potential Applications in Cancer Therapy
GABRIEL SICA and LIEPING CHEN
Abstract. 4?1BB (CD137) is a member of the tumor necrosis factor receptor (TNFR) superfamily that is expressed primarily on activated T cells. Crosslinking of the 4?1BB receptor activates an intracellular signal cascade that leads to the activation of NF?kB and costimulation of T cell growth. Recent evidence indicates that 4?1BB may preferentially costimulate CD8+ T cell growth and induce cytolytic activity. The cytolytic activity induced by 4?1BB crosslinking is able to eradicate large, well?established, poorly immunogenic tumors and augments allogenic T cell responses in vivo. The 4?1BB/4?1BB ligand costimulatory pathway can provide an alternative T cell costimulatory pathway in the absence of CD28, but may physiologically function as a synergistic or complementary pathway to the CD28 costimulatory pathway. Only some of the basic immunological functions of 4?1BB/4? ?1BB ligand have been elucidated and much study is required to determine its exact role in T cell activation.
Keywords: tumor necrosis factor receptor; tumor; costimulation; T cell activation.
Cerebral Inflammation in X-Linked Adrenoleukodystrophy
MARTINA C. MCGUINNESS1 and KIRBY D. SMITH2
Abstract. X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disease that affects approximately 1 in 25 000 males. It is characterized by elevated levels of saturated very long chain fatty acids (VLCFA), i. e., >C22:0, particularly in ganglioside and cholesterol ester fractions of brain white matter and adrenal cortex. Failure of peroxisomal very long chain fatty acyl?CoA synthetase (VLCS) to activate these VLCFA prevents their degradation by peroxisomal b-oxidation. X-ALD maps to Xq28 and the gene encodes a peroxisomal membrane protein and not the gene for VLCS. The two most common forms of X?ALD are the cerebral (CER) form, with an inflammatory demyelinating reaction that resembles multiple sclerosis (MS), and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. Investigations into the nature of the cerebral inflammatory demyelinating reaction in X-ALD will be the subject of this review.
Keywords: X-linked adrenoleukodystrophy; inflammation; demyelination; cytokines; human leukocyte antigens.
Retroviruses in Autoimmune Liver Disease: Genetic or Environmental Agents?
ANDREW L. MASON, LIZHE XU, LINSHENG GUO and ROBERT F. GARRY
Abstract. Retroviruses have been implicated in the pathogenesis of several human autoimmune conditions including Sjögren’s syndrome, primary biliary cirrhosis, immune mediated diabetes, and multiple sclerosis. The human intracisternal A type particle derived from Sjögren’s syndrome patients’ salivary glands was the first retrovirus to be isolated from a human autoimmune disorder but the agent has yet to be cloned. In primary biliary cirrhosis patients, virus like particles have been observed by electron microscopy in biliary epithelium, endogenous retroviral sequences have been cloned from liver samples, and antibody reactivity to the human intracisternal A type particle has been observed in the majority of patients tested. However, there is no evidence to link the endogenous retroviral sequences in primary biliary cirrhosis patients to the retroviral antibody reactivity or virus like particles. In other patients with liver disease, reactivity to the human intracisternal A type particle was observed in a small but significant proportion of patients with hepatitis C virus infection. If the intracisternal A type particle is an endogenous retrovirus, it is interesting to speculate that hepatitis C virus infection may modulate the endogenous retroviral expression, as chronic hepatitis C has been linked with the development of Sjögren’s syndrome. Furthermore, many patients with chronic hepatitis C virus infection have reactivity to an autoantigen of unknown significance known as GOR that has protein sequence homology with both hepatitis C virus nucleocapsid protein as well as HTLV?1 gag. This may be an another example of an endogenous retroviral protein acting as an autoantigen in liver disease patients. At this time, there is little evidence to suggest that endogenous retroviruses are infectious agents that cause autoimmune disease but they may be implicated as either genetic elements or antigens. Further studies will be required to characterize the role that both exogenous and endogenous retroviruses play in the pathogenesis of autoimmune liver diseases.
Keywords: autoimmune liver disease; hepatitis C virus; human endogenous retroviruses; human intracisterial A?type particle, primary biliary cirrhosis; Sjögren’s syndrome; systemic lupus erythematosus.
Following Angiogenin during Angiogenesis: a Journey from the Cell Surface to the Nucleolus
ANTONI WIĘDŁOCHA
Abstract. Angiogenin is a potent inducer of new blood vessel formation. It binds to high?affinity endothelial cell?surface receptors and, with lower affinity, to extracellular matrix. Angiogenin is the only angiogenic factor known to exhibit ribonucleolytic activity. It belongs to the pancreatic RNase superfamily of proteins. Angiogenin is the only member of the superfamily able to stimulate angiogenesis. Although the catalytic activity of the protein is rather weak, it is critical for its angiogenic properties. Angiogenin is specifically endocytosed by endothelial cells and transported to the nucleus, where it accumulates in the nucleolus. Also, the nuclear location of the angiogenic factor appears to be necessary for its angiogenic activity. The mechanism of action of the protein seems to be unusual, since it does not fit into the current paradigm of how exogenous regulatory polypeptides, including other angiogenic factors, work. Here, the role of transport of angiogenin from the cell?surface into the nucleolus and of its intracellular/nuclear mode of action in stimulation of angiogenesis is discussed.
Keywords: angiogenesis; angiogenin; signaling; nuclear transport; nucleolus.
Genetic Basis for Rheumatoid Arthritis
DHARAM P. SINGAL, JIANPING LI and YAOHUI ZHU
Abstract. Rheumatoid arthritis (RA) is a common disabling disorder of unknown etiology. In the past 2 decades, a number of studies have examined the genetic basis for RA. One major focus of these studies has been to identify genes within the MHC class II (HLA?DR) chromosomal region, which confer susceptibility/resistance to RA. A strong association between HLA?DR4 and adult seropositive RA has been observed in majority of populations. In addition, there is evidence of a positive association between HLA?DR1 and RA. On the basis of prevalence of DR1 (B1*0101) and of subtypes of DR4 (B1*0401, B1*0404 and B1*0405), it has been suggested that a five amino acid sequence motif (QKRAA/QRRAA) from position 70 to 74 in the third hypervariable region of DRb1 molecules is associated with susceptibility to RA. These associations between RA and HLA?DR genes are however incomplete in that about 1/4 of patients do not carry RA?susceptibility DRB1 epitope. Since MHC class III region contains genes that are involved in immune response, we have recently examined the role of a number of microsatellites (D6S273, Bat2, TNFa) and HSP70 promoter region alleles in susceptibility to RA. The results demonstrate that two regions in MHC, class II (DRb1) and class III (D6S273, HSP70, Bat2, TNFa) more completely define the risk for development of RA.
Keywords: rheumatoid arthritis; HLA?DRB1; D6S273; Bat2; TNFa; HSP70.
CD8+ T Lymphocytes Against Mycobacterium tuberculosis
MICHEL R. KLEIN and KEITH P. W. J. MCADAM
Abstract. Tuberculosis (TB) is again a global health problem. Identification and characterization of the correlates of protective immunity against TB is critical for the rationale design of novel TB vaccines. There is accumulating data that CD8+ T lymphocytes are involved in the immune response against mycobacteria. Here the current state of the art is reviewed with respect to phenotype, specificity and effector mechanisms of mycobacteria?specific CD8+ T lympocytes. In addition, the first listing is presented of mycobacteria?derived CD8+ cytotoxic T lympocyte (CTL) epitopes containing sequences published up to the end of 1998.
Keywords: tuberculosis; mycobacterium; CD8; cytotoxic T lympocyte; epitope; vaccine.
Clinical Immunology
Content of Trace Elements in Serum of Patients with Carcinoma of the Larynx
BEATA ROSTKOWSKA-NADOLSKA, LUCYNA POŚPIECH and MAREK BOCHNIA
Abstract. An examination of the content of arsenic, nickel, copper, selenium, zinc, and iron in the serum of 78 patients with carcinoma of the larynx was carried out. The patients were divided into 4 groups: I – patients before treatment, II – patients after surgical treatment, III – patients after radiotherapy, IV – patients after combined treatment (surgery treatment + radiotherapy). The control group was formed of 17 patients operated for deviation of the nasal septum. Higher concentrations of arsenic, nickel and copper were found in the serum of the patients with carcinoma of the larynx before treatment (group I) as compared with the control group, whereas the concentrations of selenium, zinc and iron were lower. In the groups of patients after treatment, the highest concentrations of iron and zinc were found after surgical treatment. The level of selenium in all groups of patients was considerably lower than in the control group.
Keywords: cancer; larynx; trace elements.
Plasma Cystatin C Concentration in Non-Insulin-Dependent Diabetes Mellitus: Relation with Nephropathy
AGNIESZKA PIWOWAR, MARIA KNAPIK-KORDECKA, HENRYKA BUCZYŃSKA and MARIA WARWAS
Abstract. We determined plasma concentrations of cystatin C, b2-microglobulin – b2-MG (low molecular mass protein markers of glomerular filtration rate – GFR), creatinine (marker of GFR) and urinary N-acetyl-b-D-glucosaminidase (NAG) excretion (marker of glomerular and tubular dysfunction) in 41 non-insulin-dependent diabetic patients. A significant increase of all the measured parameters (p<0. 001, p<0. 05, p<0. 05 and p<0. 001, respectively) in comparison to the control group, was observed. In the patients with microalbuminuria, only plasma cystatin C concentration and urinary NAG excretion increased significantly in comparison to patients with normoalbuminuria. At a cut-off level of 1. 74 mg/l for cystatin C and 1. 81 U/g creatinine for NAG (95% percentile of the normoalbuminuric group), the sensitivity of the tests for detecting microalbuminuria was 82% for cystatin C and 86% for NAG. The specificities were 88 and 92%, respectively. The present study demonstrated that determination of plasma cystatin C might be useful in the detection of incipient diabetic nephropathy and is a potentially better marker than creatinine or b2-MG. No correlation between parameters measured in plasma or urine and glycated hemoglobin was found.
Keywords: cystatin C; b2-microglobulin; N-acetyl-b-D-glucosaminidase; diabetic nephropathy.
Vol. 47, No. 6, 1999
Review
Gene Therapy with Herpes Simplex Virus Vectors
DAVID S. LATCHMAN
Abstract. Gene delivery to the nervous system represents perhaps the ultimate challenge of gene therapy in view of the complexity of this system, the wide variety of intractable neurological diseases and the need to deliver the gene to non?dividing cells. Although a variety of systems for such gene delivery are under development, herpes simplex virus has unique advantages in terms of its large genome size and its ability to enter a latent state in neuronal cells. Considerable progress has been made in the effective disablement of this virus whilst retaining its ability to deliver genes and in producing long term expression of the foreign gene. Although much remains to be achieved in the further disablement of the virus and its testing in rodent and primate models of human diseases, it is likely that these viruses may ultimately be of use in human gene therapy procedures for otherwise intractable neurological diseases.
Keywords: gene therapy; herpes simplex virus; virus vectors.
Transcriptional Control of MHC Genes and T Cell Development in MHC Class II Deficiency
BARBARA GODTHELP, MARJA C. J. A. VAN EGGERMOND, SAM J. P. GOBIN and PETER J. VAN DEN ELSEN
Abstract. MHC class II deficiency has proven to be an excellent model to study transcription regulation of MHC genes and T cell development. Cell lines established from MHC class II deficient patients have been of great value for the identification of proteins necessary for MHC expression and their study has resulted in the identification of a common regulatory pathway for MHC class II and class I genes. The lack of MHC class II expression was found to have a profound effect on the development of the CD4+ T cell lineage, in particular on the composition of the T cell receptor repertoire, revealing aberrant thymic selection processes in these patients. Here, we will discuss several aspects of the transcriptional regulation of MHC genes and the impact of deficient MHC class II expression on T cell development.
Keywords: bare lymphocyte syndrome; MHC class II deficiency; MHC gene regulation; T cell development.
Genomic Catastrophism and the Origin of Vertebrate Immunity
AUSTIN L. HUGHES
Abstract. Genomic catastrophism is the belief that unique genetic events, unlike those observed in recent evolutionary history, played a key role in the origin of vertebrate adaptations. Catastrophist hypotheses have been particularly popular is accounting for the origin of vertebrate specific immunity. Two major such hypotheses involve genome duplication by polyploidization and horizontal gene transfer. Recent analyses lead to decisive rejection of the widely cited hypothesis that the vertebrate genome underwent two rounds of genome duplication, and theoretical considerations suggest that genome duplication is unlikely to lead to new adaptive advances. Likewise, the evidence that key elements of the vertebrate immune system arose by horizontal transfer from a bacterium or by incorporation of a transposable element into the vertebrate genome remains relatively weak. Thus, at present, a uniformitarian view of the origin of the vertebrate immune system seems more reasonable, especially given the longer time?frame for vertebrate evolution indicated by molecular data.
Keywords: genome duplication; horizontal gene transfer; immune system evolution; vertebrate evolution.
Theory and Treatment of the X-Inactivation Chimera in Female-Prevalent Autoimmune Disease
JEFFREY J. STEWART
Abstract. The vast majority of patients with systemic autoimmune diseases such as Sjögren’s syndrome and systemic lupus erythematosus are female. The female prevalence of such autoimmune diseases is poorly understood. In theory, X-chromosome inactivation and resultant tissue chimerism may explain the female predisposition to systemic autoimmunity. For example, autoreactive T cells may fail to be tolerized by self antigens encoded by one of the two X chromosomes (the Kast conjecture). In the periphery, these autoreactive T cells may stimulate B cells expressing the target X-encoded antigen, so the Kast conjecture can be extended to explain how systemic autoimmunity may be induced. Another hypothesis proposes the X-encoded genes cause autoimmunity by affecting B or T cells directly; however, significant evidence has been raised discrediting this hypothesis. An attractive feature of X-inactivation hypotheses is that the discordance rate between monozygotic twins may readily be explained, because otherwise-identical twins may have different X-inactivation patterns. Reviewed here are the immunobiology of X-inactivation chimerism and its roles, both known and postulated, in autoimmune disease. Also discussed are methods appropriate for determining the cellular and molecular targets of autoreactive T cells in female-prevalent autoimmune diseases and methods by which these targets might be used as tolerogens to treat these diseases.
Keywords: X-chromosome inactivation; dendritic cells; systemic autoimmune disease; chimerism; systemic lupus erythematosus; Sjögren’s syndrome.
Clinical Immunology
Influence of Transplantable Melanomas on the Secretion of Cytokines by Hamster Peritoneal Macrophages
KRYSTYNA KOZŁOWSKA, MIROSŁAWA CICHOREK and MAŁGORZATA ZARZECZNA
Abstract. The subject of the study was the influence of two lines of transplantable melanomas on the secretion of cytokines (IL?6, TNF?a, OSM) and total proteins by hamster peritoneal macrophages. The results showed a statistically significant increase of total protein content and decrease of cytokine content in the supernatants of 24 h cultured macrophages from melanoma?bearing animals in comparison with control macrophages. Changes in the secretory function were more marked in the case of macrophages from hamsters bearing amelanotic melanoma. This may suggest that the biological features of melanomas can influence peritoneal macrophages to release the particular cytokines at different levels.
Keywords: interleukin 6; tumor necrosis factor a; Oncostatin M; peritoneal macrophages; transplantable melanomas.
Chemokine RANTES in Atopic Dermatitis
JOANNA GLÜCK and BARBARA ROGALA
Abstract. Chemokines play a key role in inflammatory diseases. The aim of this study was to estimate chemokine RANTES in the sera of patients with atopic dermatitis (AD) and to analyze the correlation between RANTES serum level and the immunological and clinical parameters of the disease. Serum levels of RANTES (ELISA; R&D Systems), total IgE and specific IgE (FEIA; Pharmacia CAP System) were estimated in 24 patients with AD, 28 patients with pollinosis (PL) and 22 healthy nonatopic subjects (HC). The division of the AD group into a pure AD (pAD) subgroup, without a coexisting respiratory allergy, and a subgroup of patients with AD and a respiratory allergy (AD+AO) was done according to Wütrich. Levels of RANTES were higher in the AD group than in the HC group and the PL group. RANTES levels did not differ among subgroups with various clinical scores and between the pAD and AD+AO subgroups. There were no correlations between levels of RANTES and total IgE. Significant positive correlations between serum levels of RANTES and Dermatophagoides farinae and cat dander?specific IgE were found in the AD group. We conclude that the serum level of chemokine RANTES differs patients with AD from patients with PL. The increase of RANTES concentration in the serum of patients with AD depends neither on a clinical picture nor an IgE system.
Keywords: allergic inflammation; atopic dermatitis; chemokine RANTES; IgE.
Role of Adhesion Molecules in Chronic Allograft Rejection
MARIA NOWACZYK, ANDRZEJ GÓRSKI, MAGDALENA DURLIK, JANUSZ WYZGAŁ and AGNIESZKA PERKOWSKA-FRANCKA
Abstract. Endothelial adhesion molecules play an important role in T cell recruitment to an allograft site. Therefore, it could be expected that their blocking may be beneficial for allograft survival. In this report, we show that T cells from patients with chronic rejection have an up-regulated ability to adhere to inflamed endothelium in vitro. Furthermore, this enhanced T cell: endothelial interaction could be blocked by anti-VCAM and anti-E-selectin monoclonal antibodies.
Keywords: anti-VCAM-1; anti-ICAM-1; anti-E-selectin; endothelium; adhesion T cells; chronic rejection.
Colostrinin®: a Proline?Rich Polypeptide (PRP) Complex Isolated from Ovine Colostrum for Treatment of Alzheimer’s Disease. A Double?Blind, Placebo?Controlled Study
JERZY LESZEK, ANNA D. INGLOT, MARIA JANUSZ, JÓZEF LISOWSKI, KATARZYNA KRUKOWSKA and JERZY A. GEORGIADES
Abstract. A proline?rich polypeptide (PRP) complex, subsequently called Colostrinin®, was isolated from ovine colostrum. The complex showed immunomodulatory properties in mice, rats, and chickens, inducing maturation and differentiation of thymocytes. It was recently found that Colostrinin® is a cytokine?like factor that acts as an inducer of interferon g (IFN?g) and other cytokines in human peripheral blood and cord blood leukocyte cultures and has psycho?immuno?enhancing activity in volunteers. These observations prompted us to study the effect of Colostrinin® on patients with Alzheimer’s disease (AD). Forty six AD patients were divided into 3 groups and randomly assigned to receive orally either Colostrinin® (100 mg per tablet, every second day), commercially available bioorganic selenium (100 mg selenium per tablet, every second day) or placebo tablets. One cycle of the treatment lasted 3 weeks and was separated from the next cycle by a 2 week hiatus. Each patient received 10 cycles of treatment during the year of the clinical trial. Outcomes were assessed by psychiatrists blinded to the treatment assignment. Eight of the 15 AD patients treated with Colostrinin® improved and in the 7 others the disease had stabilized. In contrast, none of the 31 patients from the selenium or placebo groups with similar mild or moderate AD improved. The administration of selenium promoted stabilization in 13 of the 15 patients, whereas in the placebo group only 8 of the 16 patients were stabilized at the 12 month trials end?evaluation. Colostrinin® was found to be a remarkably safe drug. Mild and transient effects were anxiety, stimulation, insomnia, and tiredness. The results obtained showed that oral administration of Colostrinin® improves the outcome of AD patients with mild to moderate dementia. The results are very encouraging and deserve further research.
Keywords: a proline?rich polypeptide (PRP) complex – Colostrinin®; Alzheimer’s disease; therapy.