CONTENTS
Review
- The NFkB/IkB System in Acute Inflammation
ALEX B. LENTSCH1, PETER A. WARD2Abstract. The transcription factor NFkB is a primary regulator of a wide variety of proinflammatory mediators. Under normal conditions, NFkB is retained in the cytoplasm bound to inhibitory proteins of the IkB family. Following cell activation, a number of signal transduction pathways lead to degradation of IkB proteins which results in nuclear translocation of NFkB and the ensuing transcriptional activation of proinflammatory genes. Several endogenous regulatory mediators, which function to prevent uncontrolled inflammation, exert their effects by blocking the activation of NFkB. Thus, NFkB appears to be at the heart of the acute inflammatory response. The present review discusses the role of NFkB in the induction and propagation of the acute inflammatory response as well as the regulation and resolution of this process.
Keywords: acute inflammatory response; transcription factor; inhibitory IkB proteins.
- Chemokines, G Proteins and Natural Killer Cells
AZZAM A. MAGHAZACHIAbstract. Natural killer (NK) cells are anti-tumor and anti-viral effector cells. Members of C, CC, CXC and CX3C chemokines induce the chemotaxis and enhance the cytotoxicity of NK cells, suggesting that these cells express receptors for chemokines. The ability of members of chemokines to inhibit the replication of HIV-1 strains, combined with the ability of the same chemokines to activate the anti-viral NK cells, provide compelling evidence for the role of NK cells in eradicating HIV-1 infection. In addition, chemokines induce various intracellular signaling pathways in NK cells, which include activation of the heterotrimeric, and perhaps the small guanine nucleotide binding (G) proteins, as well as the mobilization of intracellular calcium, among other activities. Further, chemokines induce the phosphorylation of chemokine receptors through the recruitment of G protein-coupled receptor kinases (GRKs) resulting in the desensitization and turning off the signals. In this review, I will update the knowledge of the effect of chemokines on NK cell motility and the signal transduction pathways induced by chemokines in these cells.
Keywords: chemokines; natural killer cells; G proteins; chemotaxis; cytolysis.
- Immune Privilege or Inflammation? The Paradoxical Effects of Fas Ligand
JOE O’CONNELLAbstract. Fas ligand (FasL) induces apoptosis of cells, including activated lymphocytes, expressing its cognate receptor, Fas (CD95/APO-1). FasL precludes inflammatory reactions from immune privileged sites by triggering Fas-mediated apoptosis of infiltrating proinflammatory cells. Aberrant expression of FasL by cancers inhibits antitumor immune responses. The ability of FasL to impair immune responses may hold therapeutic promise as a means of protecting tissue transplants from immunological rejection. Paradoxically, FasL exhibits proinflammatory activity independent of its ability to mediate immune privilege. FasL has been shown to recruit and activate neutrophils, although the factors that determine whether FasL is pro- or anti-inflammatory are only beginning to emerge. FasL appears to contribute to cell death in Fas-sensitive endorgan cells during inflammation. Blocking of Fas-mediated endorgan apoptosis or enhancing Fas-mediated apoptosis of inflammatory cells represent potential targets for future antiinflammatory therapies.
Keywords: Fas (CD95/APO-1); Fas ligand (FasL); apoptosis; immune privilege; transplantation; inflammation.
- Immunotherapy of Inflammatory Bowel Diseases: Current Concepts and Future Perspectives
MARKUS F. NEURATHAbstract. The etiology and the pathogenesis of inflammatory bowel diseases (IBD), e. g. Crohn’s disease and ulcerative colitis are still not completely understood. However, there is growing evidence that an alteration of the mucosal immune system towards luminal antigens in a genetically susceptible host plays a key role in the pathogenesis of IBD. In particular, cytokines produced by intestinal epithelial cells, lamina propria macrophages and CD4+ T cells appear to contribute to the initiation and perpetuation of intestinal inflammation in IBD. This review focuses on the role of the mucosal immune system in the pathogenesis of IBD and potential novel immunotherapeutic strategies for chronic intestinal inflammation. Such strategies include recombinant antiinflammatory cytokines, neutralizing antibodies or fusion proteins, antisense oligonucleotides and adenoviral gene transfer.
Keywords: Crohn’s disease; ulcerative colitis; cytokines; immunotherapy; gene transfer.
- Tumor Vaccines for the Management of Prostate Cancer
DOUGLAS G. MCNEEL and MARY L. DISISAbstract. Prostate cancer is a significant health problem and one of the leading causes of cancer-related death among men. Given the typically long natural history of the disease, there is considerable interest in developing new therapies to treat or prevent metastatic disease, and cancer vaccines are a particularly attractive immune-based approach. Early clinical studies using non-specific immunomodulatory treatments have met with limited success, but also suggest that improved immunologic approaches might be useful in treating human prostate cancer. Over the last decade, the identification of immune cells responsible for actual destruction of prostate tissue and advances in immunologic and molecular techniques have led to a variety of vaccination approaches that are currently being evaluated in human clinical trials. The present article discusses the rationale in animal models for particular immunization strategies and describes the vaccines currently being used in patients with prostate cancer. The ongoing identification of tumor antigens and proteins involved in prostate cancer progression and the development of better immunologic animal models suggest a hopeful future for the design of effective prostate cancer vaccines.
Keywords: prostate cancer; tumor vaccines; clinical trials; immunotherapy.
- The Genes of Interferons and Interferon-Related Factors: Localization and Relationships with Chromosome Aberrations in Cancer
OLGA HAUSAbstract. The paper presents a review of data on the localization of interferons (IFNs) and IFN system genes and their relationship with human diseases, mainly cancer. Genes of interferon system proteins are located at the sites of breakpoints of the structural chromosome aberrations in cancer. Thus, any of them are rearranged or translocated in various tumor types. As the activity of these genes plays a role in cancer development, their rearrangements may be one of the crucial points in the pathogenesis of some cancer types. Besides, they also take part in organism immunity against viral infections. Transfection experiments with IFN system genes have proved the influence of these genes on cancer behavior and may serve as a basis for clinical gene therapy. IFN-a and IFN-b genes are located at 9p21-22, the site of frequent homozygotic deletions in cancer. Their loss sensitizes cells to the growth inhibitory actions of exogenous IFNs. The IFN-g gene, a representative of class II genes, is located at 12q24. 1. Transfection of class II IFNs genes to cancer cell lines causes cell proliferation arrest and augments the expression of HLA antigens, which may be clinically useful in stimulating the immune destruction of tumor cells. The interferon regulatory factor 1 (IRF-1) gene is located at 5q31, the site of common deletions in myelodysplastic syndromes (MDS) and secondary leukemias. The loss of heterozygosity of this gene was found in MDS, which proves that IRF-1 may be a tumor suppressor. A transfection of its gene causes neoplastic transformation arrest. The double-stranded RNA-activated protein kinase (PKR) gene is located at 2p21-22, a region which is frequently rearranged in leukemia. Transfection of a wild type PKR gene reverses neoplastic transformation caused by transfection of a mutated PKR gene, proving that PKR acts as a dominant negative cancer suppressor.
Keywords: interferon system; gene localization; gene transfer; cancer; chromosome aberrations.
Clinical and Experimental Immunology
- Interleukin 6, Tumor Necrosis Factor a and Their Soluble Receptors in the Blood Serum of Patients with Denture Stomatitis and Fungal Infection
JAN KRZYSZTOF PIETRUSKI1, MAŁGORZATA DOROTA PIETRUSKA2, EWA JABŁOŃSKA3, PAWEŁ SACHA4, MARIA ZAREMBA and WANDA STOKOWSKAAbstract. Determinations of the blood serum levels of interleukin 6 (IL-6), tumor necrosis factor a (TNF-a) and their soluble receptors (sIL-6R, sTNFR) in denture stomatitis patients (DS) were performed. Serum levels of interleukins and their soluble receptors were measured using the ELISA method. In all examined patients mycological diagnostics were conducted using API 20C AUX stripe tests and an automatic ATB machine. Results were compared with those of healthy denture weares (D), and controls (C). In DS patients, yeasts were isolated in 90. 9%, in D in 66. 7% of cases. The most often isolated species in both groups was Candida albicans. Mean concentrations of IL-6 and TNF-a were statistically significantly higher in D and D groups compared to controls. Mean concentrations of sIL-6R were similar in all groups; however, concentrations of sTNFR in both DS and D groups were significantly lower compared to controls. There were no correlations found between values of IL-6 and TNF-a nor between examined interleukins and their soluble receptors.
Keywords: denture stomatitis; fungal infection; interleukin 6; tumor necrosis factor; soluble receptors.
- Histamine Receptor Expression on Peripheral Blood Lymphocytes Is Influenced by Specific and Nonspecific Activation
TERESA ŻAK-NEJMARK1, MARIA KRAUS-FILARSKA1, JÓZEF MAŁOLEPSZY1, RENATA JANKOWSKA2, MAREK JUTEL1, IWONA A. NOWAK1 and GRAŻYNA NADOBNA1Abstract. Histamine is a physiological mediator which exerts both effector and regulatory functions through its receptors on various cells. The aim of the study was to investigate changes in histamine receptor expression on peripheral blood lymphocytes affected by stimulation with both specific and nonspecific stimuli. Lymphocytes were obtained from both healthy and allergic subjects. Cells were incubated with various allergens (mixed grass pollen, Lolium perenne, Dermatophagoides pteronyssinus 1, bee venom, phospholipase A2) and nonspecific (fMLP, PMA/ionomycin, LPS) stimuli. The percentage of histamine-binding cells was determined with a fluorescence microscope after incubation with histamine-fluorescein. In control subjects histamine binding after stimulation with allergens was not significantly changed. In contrast, in allergic subjects stimulation with specific allergens resulted in significantly increased histamine binding. Nonspecific stimulation caused increased histamine binding to lymphocytes in both allergic subjects and healthy controls. We conclude that specific and nonspecific activation of lymphocytes is associated with increased expression of histamine receptors.
Keywords: histamine receptors; lymphocytes; specific activation.
- The Contribution of Endotoxins Present in the Respiratory Tract to Overproduction of Nitric Oxide Associated with Impaired Interleukin 6 Release in Bronchoalveolar Leukocytes from Lung Cancer Patients
MONIKA CEMBRZYŃSKA-NOWAK1, MAŁGORZATA BIEŃKOWSKA1, BOŻENA WERYŃSKA2, TOMASZ DYŁA2 and RENATA JANKOWSKA2Abstract. The purpose of the study was to assess the relation between the levels of endotoxins circulating in airways of patients with lung cancer and the ability of bronchoalveolar lavage (BAL) leukocytes for ex vivo release of nitric oxide (NO) and interleukin 6 (IL-6) and for in vitro lipopolysaccharide (LPS) -induced production of the mediators. Leukocytes isolated from the BAL of 11 patients and from 5 healthy individuals were cultured in the absence or presence of LPSE. coli. The levels of endotoxins in the BAL fluids (BALF) and the amounts of NO released ex vivo from unstimulated cells from the patients were highly (p = 0. 0025) elevated in comparison with those from healthy individuals. The release of NO was significantly correlated (Rs = 0. 638, p = 0. 047) with the levels of endotoxins in BALF. In contrast, production of IL-6 remained very low and a negative correlation (Rs = –0. 623, p = 0. 0542) was observed between the amounts of NO and IL-6. It was also found that, in response to LPS, bronchoalveolar leukocytes from patients with lung cancer express a reduced capacity for in vitro production of NO and IL-6. Our data suggest that, in patients with lung cancer, the activation of BAL cells by endotoxins circulating in the airways may contribute, at least in part, to overproduction of spontaneous NO and, subsequently, the NO may reduce IL-6 production. Moreover, the exposure in vivo of the BAL cells to LPS renders them unable to respond to the second signals.
Keywords: endotoxins; respiratory tract; nitric oxide; interleukin 6; bronchoalveolar leukocytes; lung cancer.
- T Cell Depleted Haploidentical Bone Marrow Transplantation for the Treatment of Children with Severe Combined Immunodeficiency
ELŻBIETA M. SMOGORZEWSKA, JUDITH BROOKS, GERALYN ANNETT, NEENA KAPOOR, GAY M. CROOKS, DONALD B. KOHN, ROBERTSON PARKMAN and KENNETH I. WEINBERGAbstract. Severe combined immunodeficiency (SCID) is fatal in early childhood if unrecognized and if not treated. The aim was to determine the efficacy of T cell depleted bone marrow transplantation (TCD BMT) in the treatment of children with SCID. Eleven children diagnosed with SCID received histocompatible related donor bone marrow transplantation – HRD BMT (group I). Thirty seven children diagnosed with SCID who did not have histocompatible donors were treated with TCD haploidentical parental bone marrow transplantation (BMT) (group II). TCD was performed by in vitro soybean lectin agglutination followed by E-rosette depletion. Patients were longitudinally assessed for the presence and function of T and B lymphocytes. In group I all children survived. The mean age of children in this group at the time of HRD BMT was 15. 4 months. All surviving patients normalized their specific T cell function. Two out of 11 require treatment with intravenous immunoglobulin i. v. Ig. In group II 17 out of 37 (46%) children survived. At the time of TCD BMT the mean age of survivors was 7. 5 months, vs. 11. 4 months in patients who died. Death was caused most commonly by opportunistic infections, Epstein-Barr virus induced lymphoproliferative disease (EBV-LPD), and graft versus host disease (GvHD). Seventeen out of 17 surviving patients recovered normal numbers of CD3+ cells and antigen specific T cell function. Five out of 17 never recovered their B cell function and require i. v. Ig injections. Early diagnosis, prevention or treatment of opportunistic infections, and enhancement of immune recovery will be necessary to improve survival in patients with SCID treated with TCD BMT.
Keywords: severe combined immunodeficiency (SCID); histocompatible bone marrow transplantation; T cell depleted haploidentical bone marrow transplantation.
- The Contribution of Endotoxins Present in the Respiratory Tract to Overproduction of Nitric Oxide Associated with Impaired Interleukin 6 Release in Bronchoalveolar Leukocytes from Lung Cancer Patients
MONIKA CEMBRZYŃSKA-NOWAK1, MAŁGORZATA BIEŃKOWSKA1, BOŻENA WERYŃSKA2, TOMASZ DYŁA2 and RENATA JANKOWSKA2Abstract. The purpose of the study was to assess the relation between the levels of endotoxins circulating in airways of patients with lung cancer and the ability of bronchoalveolar lavage (BAL) leukocytes for ex vivo release of nitric oxide (NO) and interleukin 6 (IL-6) and for in vitro lipopolysaccharide (LPS) -induced production of the mediators. Leukocytes isolated from the BAL of 11 patients and from 5 healthy individuals were cultured in the absence or presence of LPSE. coli. The levels of endotoxins in the BAL fluids (BALF) and the amounts of NO released ex vivo from unstimulated cells from the patients were highly (p = 0. 0025) elevated in comparison with those from healthy individuals. The release of NO was significantly correlated (Rs = 0. 638, p = 0. 047) with the levels of endotoxins in BALF. In contrast, production of IL-6 remained very low and a negative correlation (Rs = –0. 623, p = 0. 0542) was observed between the amounts of NO and IL-6. It was also found that, in response to LPS, bronchoalveolar leukocytes from patients with lung cancer express a reduced capacity for in vitro production of NO and IL-6. Our data suggest that, in patients with lung cancer, the activation of BAL cells by endotoxins circulating in the airways may contribute, at least in part, to overproduction of spontaneous NO and, subsequently, the NO may reduce IL-6 production. Moreover, the exposure in vivo of the BAL cells to LPS renders them unable to respond to the second signals.
Keywords: endotoxins; respiratory tract; nitric oxide; interleukin 6; bronchoalveolar leukocytes; lung cancer.
- RM-11, a New Izoxasole Derivative, Is a Potent Stimulator of the Humoral and Cellular Immune Responses in Mice
STANISŁAW RYNG1, ZOFIA SONNENBERG2 and MICHAŁ ZIMECKI2
Abstract. In this report we describe immunostimulatory properties of RM-11 in several in vivo and in vitro tests in the murine model. We found that RM-11 significantly stimulated the humoral immune response to sheep erythrocytes (SRBC) when given intraperitoneally (i. p.) at doses of 10 and 100 mg or per os (doses of 20 and 200 mg) 3 h before immunization. The compound was also stimulatory with regard to generation of delayed type hypersensitivity (DTH) to SRBC when given i. p. or per os (doses of 10, 100 and 500 mg/mouse). The described immunostimulatory activities of RM-11 were higher compared to that of the reference drug, levamisole. RM-11 stimulated, in addition, concanavalin A (ConA) -induced splenocyte proliferation. Lastly, we showed that RM-11 was not toxic when given to mice per os at doses 250 mg/kg body weight. Taken together, RM-11 appeared to be a universal stimulator of the immune response in mice. Lack of toxicity and the ability to stimulate the immune response, when administered per os, predispose the compound for further preclinical studies.
Keywords: stimulation; humoral; cellular immune response; izoxazole.