CONTENTS
Review
- Minor Transplantation Antigens: Mouse Models for Human Host-Versus-Graft, Graft-Versus-Host and Graft-Versus- Leukemia Reactions
ELIZABETH SIMPSONAbstract. Minor transplantation or histocompatibility (H) antigens are barriers to the transplntation of organs and tissues between genetically non-identical individuals who are matched for transplntation antigens encoded by the major histocompatibility complex (MHC), H2 in mice and HLA in humans. Recognition of minor H antigens by T cells can lead to host-versus-graft (HvG) rejection of organs and, in bone marrow transplantation, to life theatening graft-versus-host (GvH) reactions, although if these can be controlled, clinically useful graft-versus-leukemia (GvL) reactions can be obtained. This review describes the early in vivo studies that laid the foundations of our understanding that minor H antigens are the product of genetic polymorphisms, the subsequent in vitro work which has identified these at the molecular level as peptides presented to T cells by self MHC molecules, and the most recent developments, which have seen the use of minor H specific T cells clones and Sophisticated biochemical and molecular biological approaches to identify genes encoding them.
Keywords: transplantation; minor histocompatibility antigens; HY; mitochondrial antigens; T cells; expression cloning; graft-versus-host; host-versus-graft; graft-versus-leukemia; peptide epitopes; major histocompatibility complex.omplex.
- Novel Protein Toxin-Based Strategy for Development of Cytotoxic T Lymphocyte Vaccines
ANTONI WIĘDŁOCHAAbstract. Specific activation of CD8+ cytotoxic T lymphocytes (CTL) iscrucial to elicit immunity against intracellular pathogens including viruses, bacteria and protozoa. CTLs recognize mainly intracellularly processed peptides of pathogen origin associated with histocompatibility complex class I molecules (MHC class I) at the cell surface infected cells. It implicates the way how to induce specific CTL response and develop an efficient vaccine against intracellular pathogens.Therefore, the general strategy is to mimic the infection by introducing thetarget antigen into the cytosol of host cells in vivo. Several approaches have been proposed so far, including self replicating vectors, adjuvants and liposomes. However, none of them are ready for practical use. Recently, it has been shown that a number of protein toxins can be used to carry passenger proteins across cellular membranes into the cytosol. This suggested new possibilities for how to deliver a protein antigen into the cytosol for intracellular processing and presentation by MHC class I and to develop CTL vaccines. Here the use of protein toxins as translocation vehicles for delivery of antigen peptides into the cytosol is discussed. Experimental data already obtained demonstrating in vivo elicited immunity by the toxin systems are reviewed and considered.
Keywords: CD8+ T cells; protein toxins; MHC class I; antigen; vaccine.igen; vaccine.
- Interferon a in the Treatment of Chronic Myelogenous Leukemia
TADEUSZ ROBAKAbstract. Fifteen years ago Talpaz and colleagues were the first to determine that natural interferon a (INF-a ) induces hematologic remission in chronic phase patients with chronic myeloid leukemia (CML). Further research revealed that this agent, contrarily to conventional chemotherapy with busulfan or hydroxyurea, eliminates leukemic hematopoietic cells having Philadelphia chromosome (Ph1-positive) in about 20% of patients, leading to the phase of cytogenetic remission. Comparison of the efficiency of IFN-a with conventional chemotherapy was carried out in several randomized clinical trials. It was found, that IFN-a delays the occurrence of blastic phase of CML and prolongs patients life span. It does not create, however, a likely chanse of full recovery. The results of the randomized trails, carried out in France, showed that the combination of IFN-a and cytarabine as compared with INF-a alone, increases the rate of major cytogenetic response and prolongs survival in the chronic phase of CML has not been proven so far, although this drug may be of certain value in combination with hydroxyuera or other cytostatic agents. At present, it is more often considered that IFN-a should be a first line therapy in newly diagnosed CML in it’s chronic phase, if due to absence of appropriate donors or advanced age, allogenic bone marrow transplantation cannot be performed.
Keywords: chronic myelogenous leukemia; interferon a treatment; mechanism of action; randomized trials.
- Alterations in Signal Transducing Molecule CD3x in Patients with Neoplastic Diseases
IRENA FRYDECKA, PAWEŁ KACZMAREK, DOROTA BOĆKO, AGATA KOSMACZEWSKA and LIDIA CISZAKAbstract. The impairmentof immune cell functions in cancer patients may result impairment of signal transduction. Recent studies have demonstrated altered expression and function of signal transduction molecule CD3x in T and natural killer cells in patients with neoplastic diseases. Tumor infiltrating lymphocytes are more affected than peripheral blood lymphocytes. CD3x expression is more prominent in advanced stage of the disease and correlates with reduced proliferative response, IFN-g , IL-2, TNF-a production.
Keywords: CD3x ; neoplastic diseases.
Clinical Immunology
- Oral Treatment of Rats with Bovine Lactoferrin Inhibits Carrageenan-Induced inflammation; Correlation with Decreased Cytokine Production
MICHAŁ ZIMECKI, RYSZARD MIĘDZYBRODZKI and STANISŁAW SZYMANIECAbstract. The aim of this study was to investigate an effect of oral treatment of rats with bovine lactoferrin (BLF) on carrageenan-induced inflammation. Rats were given 5 oral does of BLF (10 mg each) on alternate days and 24 h after the last dose a carrageenan inflammation was induced in the hind foot. Control rats were given 0.9% natrium chloride (NaCl) or bovine serum albumin (BSA). The magnitude of the reaction was measured after 2 h (optimal response) and expressed as an increase of the foot pad thickess in milimeters. The evaluation of BLF effects on carrageenan reaction was sopplemented by determination of the ability of spleen cell cultures to produce interleukin 6 (IL-6) and tumor necrosis factor a (TNF-a ) upon lipopolysaccharide (LPS) induction using bioassays. The results revealed an inhibition of the carrageenan-induced inflammation in BLF-treated rats by 50 and 40 % as compared to NaCl and BSA control groups, respectively. The inhibition was also decreased, although to a lessre degree (48 and 35%, respectively). The decreased ability of spleen cells to produce inflammatory cytokines in BLF-treated rats indicates that hyporeactivity of the immune system cells may be the basis for the inhibition of carrageenan-induced inflammation.
Keywords: bovine lactoferrin; carrageenan inflammation; rats; interleukin 6; tumor necrosis factor a .
- Exogenous Interleukin 2 Regulates Interleukin 6 and Nitric Oxide but Not Interferon g and Tumor Necrosis Factor a Production in Bronchoalveolar Leukocytes from Patients with Small Cell Lung Cancer
MONIKA CENBRZYŃSKA-NOWAK, MAŁGORZATA BIEŃKOWSKA and EDWARD SZKLARZAbstract. The relationship and in situ interactions between interleukin 2 (IL-2)-regulated mediators remain unclear, particularly in lung cancer model. The purpose of the present study was to determine in vitro effect of IL-2 on the secretory activity of bronchoalveolar leukocytes from 11 patients with previously unterated small cell lung cancer (SCLC) and 9 patients wuth non-small cell lung cancer (NSCLC). Control group (n = 6) comprised patients who underwent diagnostic investigations and were free of any clinical or radiographic evidence of lung diseases. IL-2 induced secretion of mediators was compared with that following stimulation with lipopolisaccharide (LPS; 5 m g/ml) or Newcastle disease virus (NDV; 640 HU/ml). Obtained from bronchoalveolar lavages (BAL) cells were cultured for 24 – 48 h in the presence or absence of inducers. The levels of cytokines were determined in BAL cell supernatants by bioassays. Nitric oxide (NO) was estimated by colorimetric method in Griess reaction. Compared with normal controls, the spontaneous secretion of the above mediators excluding IFN-g in BAL cultures from NSCLC group was elevated by up to 20 -30-fold and further increase was observed after stimulation with LPS. However, very low secretion of cytokines and NO was found in BAL leukocyte cultures activated by IL-2. In contrast, the cells obtained from SCLC group produced little detectable levels of TNF-a (median 12.0, range 3 – 45 U/ml), IFN-g (median 3, range 3 – 12 U/ml) and IL-6 (median 15, range 6 – 45 U/ml) in response to LPS and interferons, mainly IFN-a ; (median 3, range 3 – 12 U/ml) in response to NDV. Although, upon IL-2-stimulation was observed only noteworthy production of IL-6 (median 405, range 45 – 1215 U/ml). IL-2-induced secretion of IL=6 was accompanied by up to 5-fold augmented secretion of NO in comparison with NSCLC group and healthy controls. These observations suggest that BAL cells from patients with lung cancers express a selective secretory activity and that IL-2 is an important regulatory factor of secondary production of IL-6 and NO. Utilization of IL-2 in therapeutic strategy in SCLC can lead to alterations in synthesis/release of biologically active IL-6 and NO that may contribute to the clinical settings.
Keywords: interleukin 2; interleukin 6; interferon; tumor necrosis factor; nitric oxide; bronchoalveolar leukocytes; small cell lung cancer; non-small cell lung cancer.
- Association of Interferon g, Tumor Necrosis Factor a and Interleukin 6 Serum Levels wih Systemic Lupus Erythematosus Activity
EWA ROBAK, ANNA SYSA-JĘDRZEJEWSKA, BOŻENA DZIANKOWSKA, DOROTA TORZECKA, KRZYSZTOF CHOJNOWSKI and TADEUSZ ROBAKAbstract. We investigated serum level of interferon g (IFN-g ), tumor necrosis factor a (TNF-a ) and interleukin 6 (IL=6) using an enzyme-linked immunosorbent assay (ELISA) in 59 patient with systemic lupus erythematosus (SLE) and 16 healthy controls. We examined a possible association between serum levels of these cytokines and SLE activity, as well as correlation between IFN-g concetration and the level of TNF-a and IL-6 and also IL-6 and TNF-a . TNF-a and IL-6 were detectable in all 59 patients and normal individuals and their level was significantly higher in SLE patients than in the control group (p < 0.001 and p < 0.02, respectively). In contrast IFN-g was detectable in 23 (39%) patients and in only 3 (20%) healthy individuals. We found positive correlation between serum concentration of TNF-a and IL-6 with SLE activity and no such correlation with IFN-g . We also observed positive correlation betweenserum levels of IFN-g and TNF-a , IFN-g and IL-6 as well as TNF-a and IL-6. In conclusion, an increase in the serum levels of TNF-a and IL-6 may be useful markers for SLE activity.
Keywords: interferon g ; tumor necrosis factor a ; interleukin 6; systemic lupus erythematosus; disease activity.
- TNF-a , IL-6 and IFN-g Secreted by Bronchoalveolar Leukocytes Isolated from Patients with Bronchial Asthma, Complicated by Fungal Airways Infections
MONIKA CEMBRZYŃSKA-NOWAK, JERZY LIEBHART, BERNARD BANASZEK, RAFAŁ DOBEK, MAŁGORZATA BIEŃKOWSKA and EDWARD SZKLARZ
Abstract. It is widely known that fungal airways infections may deteriorate the course of bronchial asthma. The mechanism of the phenomenom it still unclar. The aim of our studt was to assess the effect of fungal infections on the secretion of selected cytokines by bronchoalveolar leukocytes. Five patients (group FA) with bronchial asthma and Candida albicans or Aspergillus fumigatus airways infections (confirmed by bronchoscopy and culture) were included in the study. All of them were on the chronic treatment with corticosteroids (10 – 20 mg of prednison per day) and underwent everal courses of therapy with antibiotics. The control groups comprised 5 previusly untreated asthmatics without bronchial colonization with fungi (group A) as well as 5 healthy volunteers (group H). Leukocytes were isolated from bronchoalveolar lavage fluid (BALF) and cultured in the presence or absence of cytokine inducers such as phytohemagglutinin L (PHA), lipopolysaccharide (LPS) from E. coli. The activity of TNF-a , IL-6 and IFN-g were measured in the BAL cell culture suprenatans by using specific bioassays. In comparison with healthy controls the spontaneous or induced secretion of cytokines were significantly augmented in patients from group A. In contrast, the asthmatics who represented group FA demonstrated normal levels of spontaneous cytokine secretion. However, the tendency to increase of LPS and PHA-induced production was observed in BAL leukocytes from the patients. The above results support the view that beneficial effect of corticosteroid treatment in bronchial asthma may act, at least in part, by inhibition of the high spontaneous secretion of proinflammatory cytokines. Nevertheless, fungal airwaysinfections may lead to increase of LPS- or PHA-induced production of TNF-a , IL-6 or IFN-g (despite f prednison therapy) by prestimulation of the BAL cells with fungi.
Keywords: bronchial asthma; bronchoalveolar leukocytes; fungal airway infections; IFN-g ; TNF-a; IL-6; prednison.