CONTENTS
Review
- Cancer Immunogene Therapy
Hirohisa Yoshizawa, Hiroshi Kagamu and Fumitake Gejyo (Department of Medicine (II), Niigata University Medical School, Niigata, Japan)Abstract. The establishment of cancer in a host involves at least two major events: the escape of tumor cells from normal growth control and their escape from immunological recognition. Because of this nature of their development, cancer cells seem to be predominatly poorly immunogenic. In contrast to the previous idea that cancer cells express no recognizable antigens, recent progress in the identification and characterization of tumor antigens, as well as the expansion of knowledge on the cellular and molecular mechanisms of antigen recognition by the immune system, have raised the possibility of using immunotherapy to treat certain tumors. Information on these mechanisms has been obtained in three crucial areas: 1) the role of cytokines in the regulation of the immune response, 2) the molecular characterization of tumor antigens in both mouse and human tumors, and 3) the molecular mechanisms of T cell activation and antigen presentation. Such information has provided new insight into tumor immunology and immunotherapy. Furthermore, recombinant DNA technology allows for modification of the genome of mammalian cells for therapeutic purposes in several diseases. Several novel strategies have been developed to derive genetically modified tumor cells and use them as cellular vaccines to induce antitumor immunity in animal tumor models. This combined modality of genetically modified tumor cells and immunotherapy has been termed immunogene therapy of tumors. Crucial to this approach has been the ability to transfer into normal or neoplastic cells genes known to increase the immunogenicity of cells, which subsequently can be used to augment immune reactions in tumor-bearing mice or cancer patients. While there has been success in inducing antitumor immunity in some tumor models, there are difficulties and limitations in the application of these gene-modified tumor cells for the treatment of preexisting tumors. In this review, recent progress in cancer immunogene therapy is discussed.
Keywords: immunotherapy; transfection; cytokine; costimulatory molecule.
- Regulation of IL-5 expression
Viatcheslav A. Mordvinov and Colin J. Sanderson (Curtin University of Technology, Perth, Western Australia)Abstract. Interleukin-5 (IL-5) is a cytokine primarily involved in the pathogenesis of atopic diseases. It specifically controls the production, activation and localization of eosinophils, the major cause of tissue damage in atopic diseases. IL-5 belongs to a gene family shared by IL-3, IL-4 and GM-CSF and is predominantly regulated at the transcriptional level. A variety of stimuli and modulators have been identified as regulating production of IL-5 both in vivo and in vitro, indicating a highly complex series of control mechanisms. However, a better understanding of the biology of IL-5 and the regulation of its expression is crucial for the development of new therapeutic agents for allergic disease. This review covers the major molecular aspects of IL-5 research.
Keywords: interleukin 5; cytokines; allergic diseases.
- Sjogrens’s Syndrome: Imunological Response Underlying the Disease
Jason B. Brayer, Michael G. Humphreys-Beyer and Ammon B. Peck (Departments of Oral Biology and Pathology, Laboratory Science and Center for Orphaned Autoimmune Diseases, University of Florida, Gainesville, FL 32610, USA)Abstract. Sjögren’s syndrome is a chronic autoimmnune disorder characterized primarily by the discomforts od dry eyes and dry mouth due to the progressive loss of exocrine gland function. Development of a number of animal models to study Sjögren’s syndrome, especially the NOD mouse and its congenic partner strains, has permitted a systematic analysis of immunological and non-immunological factors that influence predisposition for development of the autoimmune response. These data are reviewed here.
Keywords: NOD mouse; autoimmune exocrinopathy; cytokine knock-out mice; autoantibody.
- B Cell Tolerance to Self in Systemic Autoimmunity
Moncef Zouali (Hôpital Broussais, INSERM U 430, 96 rue Didot, 75674 Paris Cedex 14, France)Abstract. After a century of research and despite intensive scrutiny, the origin of autoantibody production remains an enigma. Recently, the essential role of B cells in promoting systemic autoimmunity in mice seems more important than previously thought: self-reactive B cells can be subject to positive selection and a deficiency in serum IgM predisposes to the development of IgG antibodies to autoantigens. Studies of the B cell repertoire expressed in systemic autoimmune diseases have provided important clues. In human lupus, quantitation of this repertoire reveals the presence of an expansion of IgG clonotypes that impart reactivity with disease-related autoantigens. The nucleotide sequences of autoantibodies derived from these patients and expressing nephritogenic idiotopes (present in immune complexes and renal eluates of subjects with active disease) show features of diversification with a high rate of replacement/silent mutations and clustering of the mutations in the hypervariable regions, suggesting than an antigen-driven process plays a role in the generation of pathogenic autoantibodies. Currently, the contributions of apoptosis and of cell receptor signaling to this triggering are being appreciated. Pursuing these and related issues will have an important impact on autoimmune research.
Keywords: autoimmunity; B cells; systemic lupus erythematosus.
- HIV-Macrophage Interactions at the Cellular and Molecular Level
Makobetsa Khati, William James and Siamon Gordon (Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom)Abstract. Macrophages, centrally involved in both the innate and adaptive arms of the immune system, are not only the chief target of the human immunodeficiency virus (HIV), but also its main reservoir and vehicle of transmission. Macrophage-tropic viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of preferential T cell- and/or dual-tropic HIV-1 variants. Functional impairment of HIV-infected macrophages plays a role in the immune dysregulation characteristic of AIDS (acquired immunodeficiency syndrome). Efforts directed ant understanding the cellular and molecular mechanisms underlying HIV-macrophage interactions remain the basis for devising novel and efficacious therapeutic strategies against HIV and the AIDS epidemic.
Keywords: macrophages; HIV reservoir; immune dysregulation; AIDS.
- Mycobacterium-Specific Human CD8 T Cell Responses
Michel R. Klein and Annette Fox (Tuberculosis Research Programme, Medical Research Council (MRC) Laboratories, Atlantic Road, Fajara, PO Box 273, Banjul, The Gambia, West Africa)Abstract. Tuberculosis (TB) remains a global health problem. There is an intense effort to identify correlates of protective immunity and to design new TB vaccines. CD8 T cells are thought to play a significant role in controlling Mycobacterium tuberculosis infection. Relatively little has been published about the antigens and epitopes targeted by mycobacteria-specific CD8 T cells. Here we present an update of our 1999 overview of human CD8 T cell epitopes in mycobacterial antigens and discuss related issues relevant to TB diagnosis and vaccine development.
Keywords: mycobacterium; tuberculosis; CD8; epitope; vaccine; diagnosis.
Clinical Immunology
- The Effects of Endotoxin Administration on Cytokine Production in Obstructive Jaundiced Rats
Janusz Dawiskiba1, Michał Zimecki2, Danuta Kwiatkowska3 and Adam Kuźmiński1Abstract.
1First Clinic of General and Endocrine Surgery, Wrocław Academy of Medicine, Poniatowskiego 2, 50-326 Wrocław, Poland,
2Department of Experimental Therapy, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, Poland,
3Department of Clinical Biochemistry, Wrocław Academy of Medicine, Chałubińskiego 10, 50-368 Wrocław, PolandThe aim of this study was to evaluate the effect of lipopolysaccharide (LPS) administration, which mimics a surgical intervention, on the immune status of obstructive jaundiced (OJ) and sham-operated control rats. Rats were given 20 mg LPS intraperitoneally on day 13 following bile duct ligation or sham surgery. We determined serum levels of tumor necrosis factor a (TNF-a) and interleukin 6 (IL-6) on day 14 after surgery, and spontaneous as well as LPS-induced production of these cytokines in splenocyte and peritoneal exudate cell cultures (PEC). We found that IL-6, but not TNF-a, serum concentrations were significantly elevated (4-fold) in OJ rats treated with LPS compared with LPS-untreated OJ rats. In sham-operated rats the differences between the respective groups were not significant. The production of TNF-a by splenocyte and PEC cultures was depressed in OJ rats treated with LPS; in particular, a very deep decline was observed in the case of spontaneous TNF-a production in PEC cultures. In contrast, TNF-a production in LPS-untreated and LPS-treated sham-operated rats did not differ. In the case of IL-6 production by splenocytes and PEC cultures, we observed a significant suppression of this cellular function in both OJ and sham-operated rats treated with LPS when compared with the respective controls. In conclusion, the results indicate that the already depressed cytokine production in OJ rats leads to even deeper hyporeactivity following LPS challenge. Lack of TNF-a suppression upon LPS treatment in sham-operated rats suggests that surgery-elicited hyporeactivity is mediated by a different mechanism than that leading to immune hyporesponsiveness in OJ. Our findings may explain the relatively high mortality rates of OJ patients subjected to surgery.
Keywords: obstructive jaundice; LPS; splenocytes; peritoneal cells; TNF-a; IL-6.
- Proinflammatory Cytokines (IL-6, IL-8), Cytokine Ihibitors (IL-6 sR), sTNFR II) and Anti-Inflammatory Cytokines (IL-10, IL13) in the Pathogenesis of Sepsis in Newborns and Infants
Janusz Piotr Sikora, Danuta Chlebna-Sokół (Department of Pediatric Propedeutics, Institute of Pediatrics, Medical University of Łódź, Poland) and Alicja Krzyżańska-Oberbek (Critical Care Unit, District Hospital No. 4, Medical University of Łódź, Poland)
Abstract. The levels of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8, and the anti-inflammatory cytokines IL-10 and IL-13 were studied in child patients with sepsis. The changes of the cytokines inhibitors soluble IL-6 receptor and soluble p75 TNF alpha receptor were also investigated in the patients’ sera. An increase of pro- and anti-inflammatory cytokine levels was demonstrated at the time of diagnosis. Pharmacotherpy was accompanied by a decrease of the elevated concentrations of both cytokines and their inhibitors. The time pattern of changes in cytokine and cytokine inhibitor serum concentrations along with the time course of acute phase indices, including procalcitonin and C-reactive protein, allows for an evaluation of system inflammatory response and may support diagnostic and prognosis methods.
Keywords: sepsis; cytokines; cytokine inhibitors; children.