The role of IL-4 and IL-10 cytokines in controlling an anti-tumor response in vivo
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The effect of systemic administration of anti-inflammatory cytokines (IL-4 and IL-10) on the development and maintenance of an anti-tumor rejection response in vivo was studied by following the growth patterns of P815.B7 tumors on B6D2F1 [(C57BI/6 x DBA/2)F1] mice. The anti-P815.B7 rejection response was found to be T cell dependent, involving both CD4 and CD8 cells. IL-4 treatment resulted in a compromised rejection response; IL-10 treatment alone had little or no effect. These results demonstrate that treatment with an anti-inflammatory cytokine can compromise an otherwise effective anti-tumor rejection response. For the anti-inflammatory cytokine IL-4, the immunosuppressive effects of the cytokine appear to outweigh any possible anti-tumor activities as have been reported using tumor cells genetically altered to produce IL-4. Relatively high systemic doses of IL-10, in contrast, were not immunosuppressive and, when given in combination with IL-4, countered the IL-4 suppressive effect. Pathologically, IL-4 treatment led to splenomegaly characterized by a marked increase in neutrophils and NK activity. The possible linkages between neutrophils, NK activity and IL-12 are discussed.AbstractHIV infection is associated with both a hyperactivity of the immune system and decreased immune responses against specific antigens. A similar pattern is observed when considering cytokine production in HIV-infected patients. Several cytokines are spontaneously produced at an increased level, whereas other cytokines playing an important role during cell-mediated immune responses are produced at a low level following stimulation. This deregulation of cytokine production may participate to the immune deficiency, both by impairing immune responses and by accelerating CD4+ T lymphocyte destruction. Chemokine receptors have recently been shown to function as coreceptors for the virus, and to govern its cellular tropism. Heterogeneous expression of chemokine receptor may contribute to differences in infectability as well as in rate of progression of the disease between individuals. Better understanding of the role of cytokines and chemokines in HIV infection suggests new therapeutic approaches where administration of cytokines or cytokine antagonists may allow the immune system to function in better conditions, to stimulate antiviral and antiinfectious immune defenses, and to limit viral spread.Key Words: HIVCytokinesChemokines
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HIV infection is associated with both a hyperactivity of the immune system and decreased immune responses against specific antigens. A similar pattern is observed when considering cytokine production in HIV-infected patients. Several cytokines are spontaneously produced at an increased level, whereas other cytokines, playing an important role during cell-mediated immune responses, are produced at a low level following stimulation. This deregulation of cytokine production may participate in the immune deficiency, both by impairing immune responses and by accelerating CD4+ T-lymphocyte destruction. In addition to contributing to the immune disequilibrium of the disease, impaired cytokine production in HIV-infected patients may contribute to the emergence and to the clinical symptoms of several complications of the disease, such as opportunistic infections, Kaposi's sarcoma and lymphomas. Better understanding of the role of cytokines in HIV infection may suggest new therapeutic approaches in which administration of cytokines or cytokine antagonists may allow the immune system to function more effectively and may stimulate antiviral and anti-infectious immune defences.
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Cytokines are important soluble signalling molecules that dictate and coordinate inflammatory and immune responses. Further understanding the role of cytokines in the pathobiologic mechanisms of pulmonary inflammatory and immune diseases holds the key to the development of effective prophylactic and therapeutic strategies. In the last several years, the use of models of human pulmonary diseases established either in normal adult animals, mice deficient for a given immune cell type or cytokine, or mice engineered to overexpress a given cytokine, has remarkably facilitated our understanding of the mechanisms operating in human disease. Cytokines that are involved in pulmonary inflammatory and immune conditions may be generally divided into groups of pro-inflammatory, anti-inflammatory and growth-stimulatory cytokines. While pro-inflammatory cytokines can be detrimental under such severe conditions as endotoxemia and fibrosis, they are required in host resistance against infectious agents. Anti-inflammatory cytokines play an important role in controlling the extent of tissue inflammatory/immune responses. Overexpression of growth-stimulatory cytokines are often directly associated with tissue fibrotic responses. In this review, the findings attained from experimental models by us and others were discussed with emphasis on cellular and histopathologic alterations, cytokine-mediated molecular mechanisms and the prospects of cytokine-based therapeutic strategies. Due to the restrict space, we chose to focus only on models for endotoxic lung, endotoxemia, acute pulmonary infections by extracellular Gram-negative bacteria, chronic pulmonary infections by intracellular myco-bacteria, allergic airways inflammation and pulmonary fibrosis.
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A widely applied method to study the activation of the innate immune system is in vitro stimulation of whole blood using lipopolysaccharide (LPS). However, it is unclear if in vitro cytokine production relates to in vivo cytokine levels elicited during experimental endotoxemia or sepsis. To determine the correlation between in vitro cytokine production and the in vivo inflammatory response, blood was obtained from 15 healthy volunteers for in vitro incubation with Escherichia coli LPS, immediately followed by experimental E. coli endotoxemia. Correlations of in vitro and peak in vivo cytokine concentrations were determined using Pearson correlation coefficient. In stimulated whole blood, tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1beta, IL-6, IL-10 and interferon (IFN)-gamma were induced to 279 +/- 53, 392 +/- 64, 5312 +/- 624, 83 +/- 20 and 343 +/- 85 pg/ml, respectively, whereas in vivo cytokine induction led to cytokine levels of 603 +/- 123, 11 +/- 1, 4999 +/- 1228, 167 +/- 25 and 194 +/- 40 pg/ml, respectively. Correlation coefficients between the in vitro and in vivo cytokine concentrations were for TNF-alpha, IL-1beta, IL-6, IL-10 and IFN-gamma -0.10 (P = 0.7), 0.09 (P = 0.8), 0.36 (P = 0.2), 0.19 (P = 0.5) and 0.40 (P = 0.1), respectively. Comparison between in vitro and in vivo stimulation with LPS shows no correlation between the amount of cytokines produced. In vitro cytokine production, therefore, does not predict the in vivo inflammatory response.
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textabstractThe human body has an extensive defence mechanism (immune system) for coping with pathogens. It is regulated by signalling molecules called cytokines. Cytokines are produced by various cells of the immune system such as leucocytes (e.g. T-cells and macrophages) but also by nasal and pulmonary epithelial tissue. There are several different types of cytokines. Th1 cytokines are involved in the eradication of bacterial and viral pathogens, while Th2 cytokines are involved in the defence against parasites. The production of Th1 cytokines is suppressed by Th2 cytokines and vice-versa so that the production of both cytokines is kept in balance. An overproduction of Th1 cytokines is found in auto-immune disorders, while allergic disease is frequently accompanied by high Th2 cytokine production. Furthermore, pro-inflammatory cytokines can induce general inflammatory reactions, while anti¬inflammatory and regulatory cytokines may downregulate these responses.
Immune responses in newborns are immature. This is seen in relatively high levels of Th2 and regulatory cytokines and low levels of Th1 cytokines compared to adults. The infant immune system matures with age. This maturation process consists of a relative increase in the production of Th1 cytokines compared to Th2 cytokines. Viral respiratory infections in infants may stimulate immune matura¬tion by their repeated Th1 stimulating effect, and thereby reduce the risk of a child developing Th2-mediated allergic disease. This hypothesis was first proposed by Professor Strachan in 1989 and is known as the ’hygiene hypothesis’.In the VI¬GALL study (VIGALL is the Dutch abbreviation for virally-mediated allergy), we examined whether respiratory infections predominantly induced by viruses may affect the maturation of the immune system and the development of allergic dis¬ease. We therefore looked to see which respiratory viruses are most prevalent in infants and what types of immune response are induced in the noses of these chil¬dren during infection and when healthy. We then examined whether the number of respiratory infections and the maturation of the immune system were related.
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In article presented results of the study of basic levels of regulatory cytokines in patients with various forms of Epstein-Barr virus infection. Analysis of the dynamics of cytokine profile in patients with Epstein-Barr virus infection revealed the opposite changes studied synthesis of proinflammatory and anti-inflammatory cytokines, which was the basis for the establishment of the four types of immune response. The findings confirm the existence of cytokine imbalance with Epstein-Barr virus infection. The established types of immune responses indicate inadequate cell humoral reactivity in a long persistence of Epstein-Barr virus infection, which manifests a tendency to suppression of cell-mediated and humoral immune response enhancement mechanisms and displayed in the clinical and biochemical manifestations of the disease, and also leads to prolonged undulating course. The results of studies confirm the existence of cytokine imbalance in various forms of EBV infection. The established types of immune response indicate inadequate cellular-humoral reactivity of the organism under the conditions of long-term EBV persistence. This is manifested by a tendency to suppress cell-mediated and increased humoral mechanisms of the immune response and is displayed in the clinical and biochemical manifestations of the disease and leads to a prolonged wave-like course of the disease. Interesting and promising are studies aimed at the medical correction of identified disorders in established types of immune response in patients with HEVE and studying the effects of the latter on the outcomes of the disease, the development of complications and activity of the process, which will be the subject of our further study.
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