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EN
In our review article we intend to show the importance of IL-4, IL-5, IL-13, IL-10, IFN gamma and IL-12 in pathomechanism of allergic inflammatory process, expecially in bronchial asthma. We also want to ilustrate the relationships between lymphocytes T, monocytes, macrophages, eosinophils and other inflammatory cells which take part in allergic inflammation.
EN
We investigated the levels of 6 different cytokines in the sera of 10 newly diagnosed patients with B-cell lineage acute lymphoblastic leukemia (ALL) and detected a significant increase in IL-6 and IFN- serum levels in comparison to that of healthy controls. Whole blood cell cultures of 10 ALL patients and 20 control individuals were induced with classical cytokine inducers, such as virus, PHA and LPS, and their ability to produce 9 different cytokines was compared. Blood cells of ALL patients produced significantly less IL-1, IL-1, IL-10 and TNF- than control cells and not significanly lower levels of IL-6, but comparable with control levels of IL-2, IL-4. rHuGM-CSF added to cell cultures 24 hr before induction significantly enhanced the production of IL-1, IL-1 and TNF- in controls, but only IL-1 and IL-1 in the blood cell cultures of patients with ALL. GM-CSF did not significantly influence the production of IFN-, IFN-, IL-2, IL-4 and IL-10 in the control cells and the cells of ALL patients. The patients examined differed not only in the expression of CD10 and CD34 antigens on blast cells, but also in the reaction to GM-CSF treatment, which was found as very high standard deviation values. We suppose that these differences can partially explain the different effects of GM-CSF when used to ameliorate neutropenia of ALL patients after chemotherapy and to reduce the incidence of microbial infections.
EN
In this review we have examined the role of a variety cytokines in the pathogenesis of rheumatoid arthritis (RA) and their possible applications in the treatment of this disease. Cytokines are small protein molecules, released by activated cells which function as chemical messengers between cells of the immune, inflammatory and other systems. The studies using isolated cells from RA synovial membranes indicate that the vast majority of known cytokines are found in RA synovial tissue. These include IL-1, TNFa, IL-6, IL-8, TGFb, GM-CSF and others. TNFa and IL-1 are important 'pivotal' molecules in the disease process. TNFa has been detected in the serum and synovial fluid of patients with RA, sugesting an important contribution of this cytokine to the development of arthritis. Clinically, TNF-a has been also associated with markers of rheumatoid disease activity. Rheumatoid synovial tissue synthesizes large amounts of both forms of IL-1 (IL-1a and IL-1b) in vitro. IL-1 can exert a variety of systemic effects, including induction of fever and synthesis of acute phase proteins. It also induces local joint effects mediating production of fibroblast fibronectin and tissue collagenase. IL-6 is found in greater quantities in the synovial fluids from patients with RA compared to osteoarthritis. Synovial fluid IL-6 levels correlate with local IgM rheumatoid factor and systemic acute phase protein production. Chemokines, including IL-8, have potent chemotactic activity for cells of the immune system. IL-8 not only participates in the inflammatory phase of RA, but also participates in the vasculoproliferative phase of this disease. Recent data on the cytokine profile in RA implies that alternative treatment strategies should be considered. Potential approaches for modifying the cytokine network include inhibition of cytokine production or their action, inhibition of signal transduction and administration of suppressive cytokines.
EN
Megakaryocytopoiesis is regulated by a number of cytokines with either stimulatory or inhibitory effects. Thrombopoietin (TPO), a cytokine with specific megakaryocyte naturational activity recently has been identified as the c-Mpl ligand. The physiological role of TPO and its potential mechanism of regulation has been investigated by generating mice that are missing the gene for TPO receptor (c-Mpl) and therefore deficient in the receptor itself. In homozygous knock-out mice (c-Mpl-/-) blood platelet counts were reduced to about 85% compared to wild-type mice. Several groups have now reported on the genomic structure of the TPO locus and the gene maps to the long arm of human chromosome 3 and mouse chromosome 16. The human cDNA predicts a mature molecule of 332 aminoacids with striking homology to erythropoietin throughout the N-terminal half. Recombinant TPO has profund effects on megakaryocyte progenitors and induction of megakaryocyte maturation to the point of platelet production. Administration of recombinant TPO to redents or primates treated with myelosuppresive agents abrogates or alleviates the severity and the duration of the resultants thrombocytopenias. The in vitro and in vivo activities of the TPO indicate that this cytokine may hold a promise for prevention and treatment of thrombocytopenia associated with chemotherapy, irradiation and bone marrow transplantation.
EN
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.
EN
The aim of the study is to determine whether serum concentrations of interleukin (IL)-1 and IL-6 correlate with indices of bone mineral metabolism in children with idiopathic osteoporosis and osteopenia. The study comprised 62 patients aged 6?18 years (20 with idiopathic osteoporosis, 22 with idiopathic osteopenia, and 20 controls). In 10 children, investigations were repeated after one year of treatment. Serum concentrations of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), as well as IL-6 and its soluble receptor (IL-6sR) were determined by the ELISA method. In patients with decreased bone mass, selected calcium-phosphorus metabolism indices and bone turnover markers were assessed. Higher values of IL-6 were recorded in those with idiopathic osteoporosis than in controls (2.79 vs. 1.43; p<0.05). In these patients there was also a tendency towards higher values of IL-6sR (p=0.05). IL-1alpha and IL-1beta were not markedly elevated in any of the patients. No significant differences between groups regarding IL-1ra were observed. Negative correlation between IL-6, IL-1alpha, cytokine/receptor indices, and spinal bone mineral density was determined. Positive correlation was found between IL-?, IL-1/IL-1ra, and parathormon as well as between IL-1?, IL-6sR, and bone formation markers. Increase in bone mass after treatment was accompanied by a decrease in IL-6sR. The higher serum levels of IL-6 in children with idiopathic osteoporosis/osteopenia and the decrease in IL-6sR after treatment reveal an involvement of IL-6 in the etiopathogenesis of these disturbances. The results suggest that IL-1 may also participate in the primary decrease of bone mass in children.
EN
This article reviews the current concept in the ethiology and pathogenesis of systemic sclerosis. It is suggested that free radicals play a crucial role in pathomechanisms of scleroderma. In addition, the influence of some environmental agents (silica, bleomycin, aalcohol, toxic oil) on free radical production and subsequent induction of scleroderma or scleroderma-like syndrome is also described.
EN
The functional characterization and subsequent purification of T cell growth factor/interleukin (IL)-2 in the early 1980s established this secreted protein as a key mediator of immune cell activation and provided the prototype that enabled the discovery of numerous cytokines over the ensuing two decades. While soluble immunoregulatory factors were initially identified functionally as biological activities present in the culture supernatants of activated lymphocytes/monocytes, this methodology shifted radically following the completion of the human genome sequence. Computer-generated structural modeling algorithms have replaced functional assays and biochemical purification as the initial means of discovering new cytokines. To date, a total of 31 interleukins, as well as over a dozen other related hematopoietic factors, have been identified. These cytokines and their receptors may be grouped on the basis of structural homologies as well as by shared ligand and receptor subunits. The challenge now at hand is to define the biological functions of the newly identified cytokines and to elucidate the common and divergent roles of related family members. This point is well illustrated by the IL-12/IL-23/IL-27 family, whose members share ligand and receptor subunits and play somewhat overlapping roles in innate and adaptive immune responses. These three cytokines are not entirely redundant, as they may preferentially activate na?ve or memory T cells, induce discrete T cell cytokine profiles, contribute to distinct stages of host immune responses to infectious agents, and differentially promote autoimmunity. Further elucidation of the unique functions of the IL-12 family members may lead to improved immunodiagnostics and therapies.
EN
Stem cells offer the distinct prospect of changing the face of human medicine. However, although they have potential to form different tissues, are still in the early stages of development as therapeutic interventions. The three most used stem cell sources are umbilical cord blood, bone marrow and human embryos. Whilst, cord blood is now used to treat over 70 disorders, at the time of writing this manuscript, not a single disease has been overcome or ameliorated using human embryonic stem cells. Advancing stem cell medicine requires ethically sound and scientifically robust models to develop tomorrow's medicines. Media attention, however, distracts from this reality; it is important to remember that stem cells are a new visitor to the medical world and require more research. Here we describe the utility of human cord blood to develop neural models that are necessary to take stem cells to the next level ? into human therapies.
EN
There is a high medical need for better therapies for psoriasis. Based on new insight into the pathophysiology of this frequent immune disease, a number of novel systemic immunomodulatory therapies are currently in clinical development. These include approaches targeting antigen presentation and costimulation, T cell activation and leukocyte adhesion, action of proinflammatory mediators, and modulating the cytokine balance. Although mainly only preliminary data are available so far, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis. Moreover, since psoriasis can be considered as a visible model disease for T cell-mediated disorders characterized by a type 1 cytokine pattern in general, such approaches may have impact for other immune disorders as well. Here we review the rationale and the initial clinical data of these important recent experimental therapies.
EN
Contribution of endothelial cells to normal immune processes (circulation of leukocytes, immune diapedesis, presentation of antigenes) as well as to pathology caused by viral diseases is described.Cytokine secretion and expression of adhesion molecules, particularly during viral infections are described.Permissiveness of endothelial cells to HIV infection is presented.Contrinution of herperviruses (CMV, HSV) to thrombosis and atherosclerosos is also considered.
EN
Type I interferons (IFNs) are cytokines that induce multiple biological effects on target cells, including antiviral, antiproliferative, and immunomodulatory activities. Consistent with the pleiotropic nature of these cytokines, multiple signaling pathways are activated during binding of IFNs to the type I IFN receptor. An important signaling cascade activated by type I IFNs is the Jak-Stat pathway. Activation of the Tyk-2 and Jak-1 kinases, and downstream formation of various Stat complexes, mediates IFN-dependent gene transcription for IFN-stimulated genes. In addition to the classic Jak-Stat pathway, type I IFNs activate multiple other pathways, including the insulin receptor substrate-phosphatidylinositol 3'-kinase cascade, the CBL-CrkL pathway, and mitogen-activated protein kinase pathways. There is accumulating evidence that non-Stat IFN-regulated signaling pathways play important roles in the generation of the antiproliferative effects of type I IFNs. In this review, the regulation of various signaling cascades by the type I IFN receptor is summarized and an update on recent advances in the field is provided.
EN
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.
EN
Introduction Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma (MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production. It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells. Materials and Methods: Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-alpha production by CD166+ mesenchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor (sIL-6R), IL-11, IL-10, TNF- alpha, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and osteopontin (OPN) production in the supernatants of the cultures and co-cultures. Results A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF- alpha, OPN, and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly enhanced the production of sIL-6R by the RPMI8226 cells. Discussion Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6, IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-alpha, HGF), adhesion stimulatory factors (HGF, BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-alpha), and angiogenic factors (TNF-alpha). The results of this experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced production of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on contact with the MM cells. This in turn suggests the presence of an undefined, autocrine stimulation pathway resulting in a prolonged production of cytokines even in long-term cultures in vitro and in vivo. These abnormalities might provide optimal conditions for the proliferation and differentiation of residual tumor cells or their precursors in the affected bone marrow.
EN
It is well documented that most if not all aspects of mast cell development, including growth, proliferation, and the differentiation/maturation are regulated by cytokines. Nowadays there is growing evidence that cytokines also influence the biology and function of mature tissue mast cells. Some cytokines activate mast cells directly to mediator release or modulate their reactivity to other stimulating agents. Various cytokines affect mast cells migration and expression of cell receptors, at the same time regulating the survival of tissue mast cells. Taking into account that mast cells themselves are the source of many cytokines (both preformed and newly generated) it can be assumed that these cytokines regulate the function of mast cells in tissues in autocrine manner
EN
This present review summarises recent results investigating the role of certain cytokine gene polymorphisms, including TNF, IFN, IL-6, IL-10 and IL1 Ra, in allogeneic stem cell transplantation. The review discusses their role in predicting outcome and the development of a genetic risk index for Graft versus Host Disease in HLA matched sibling transplants. By the comparative use of an in vitro human skin explant model initial results suggest that certain cytokine gene polymorphisms may be associated with more severe disease.
EN
Sjogren'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 Sjogren'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.
EN
A cytokine produced by the subpopulation of activated helper lymphocytes T has been called interleukine-2 (IL-2).The obtaining of recombinant cytokine has facilitated the study of ita biological properties and its application in teh treatment of certain neoplastic and infectious diseases.IL-2 affects the target cells by means of a receptor of great affinity consisting of three independent chains: alpha, beta, gamma.The cytokine is the most important growth factor of lymphocytes T, conditioning their clonal expansion.Antigen stimulation in the condition for the experssion of IL-2 does not, however, affect resting lymphocytes T. The expression of teh receptor for this cytokine on NK cells is ,however, continous in character but only a very small percentage of these calls has receptors of great affinity.IL-2 plays a great role in adoptive immunotherapy consisting in intravenous administration of cell with cytotoxic properties.Cells obtained from peripheral blood and grown in vitro are called LAK cells (lymphocyte activated killer cells), while cells obtained from neoplasms and grown in similar conditions are named TIL cells (tumor infiltrated lymphocutes).LAK and TIL cells reveal a similar antineoplastic activity in vivo.At present, however, recombinat IL-2alone is used more often, either intravenously or subcuteously.The cytokine is effective in the treatment of patients with disseminate cancer of the kidney and melanoma, and in adjuvant therapy of acute myeloid leukemia.Attempts have been to apply it in the treatment of AIDA and leprosy.The toxic effect of IL-2 depends on the dose and the mode of administration.In the majority of patients parainfluenzal symptoms appear.Most undesirable effects are connected with multisystemic syndrome of capillary vessels hypermeability leading to the increasing fluid retention into extravascular spaces, oedema, hypotonia and oliguria.
EN
Serum tumor markers: CEA, CA 19-9, AFP, TPS may be helpful in early diagnosis of colorectal cancer, in the initial assesment of the extent of the disease, and in monitoring of the tumor growth or tumor volume reduction once cancer has been diagnosed and treatment started. Recent studies have focused on a new substances (candidates for tumour markers) of colorectal cancer.
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