Cytokines in the Treatment of Infectious Diseases: Options for the Modulation of Host Defense

Fourth, PMNs constitute the main effector cells in both intracellular killing of blastospores and extracellular damage to Candida hyphae and pseudohyphae and several cytokines playing a role in this process have been identified [10—12]. The influx of PMNs at the site of an invasive Candida infection is controlled by a variety of endogenous pro-inflammatory cytokines.

Recent studies have elucidated the role of IL-6 in host defense against experimental Candida albicans infection. Cell-wall components of C. These mice do not differ in their susceptibility to disseminated candidiasis compared with neutropenic control mice that do produce IL-6, indicating that PMNs are likely to be the dominant protective mechanism through which IL-6 exerts its beneficial effects [17]. Conversely, the administration of recombinant IL-6 decreases the fungal load in the organs of mice with disseminated candidiasis [16].

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It is believed that the dominance of either of the two T-helper subsets Th1 and Th2 closely correlates with the outcome of Candida infection [18]. In models of disseminated candidiasis, occurrence of Th1 responses is associated with protection, whereas Th2 responses correlate with progressive infection [19].

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IL-6 is among the cytokines that are required to induce a Th1 response and absence of IL-6 during disseminated candidiasis leads to a reduced production of IL and an increased IL release [16]. This Th2-type pattern has been shown to adversely affect the outcome of experimental disseminated candidiasis, as administration of exogenous rIL leads to increased mortality to Candida infection, whereas administration of rIL protects mice against disseminated candidiasis [20 , 21].

Thus, the regulation of neutrophil recruitment and subsequent development of cellular immunity appear to be closely related. Fas ligand FasL , a member of the TNF family, also plays a role in regulating neutrophil recruitment and host defense to candidiasis [26 , 27]. An other cytokine involved in PMN influx is IL-1 [28] , although its exact role in invasive candidiasis has not been established [29].

In addition, the hematopoietic growth factors granulocyte colony-stimulating factor G-CSF and granulocyte-monocyte colony-stimulating factor GM-CSF are undoubtedly among the most important mediators of PMN recruitment during infection [30]. G-CSF is a hematopoietic growth factor that promotes the proliferation and differentiation of neutrophils from bone marrow. The recombinant form rG-CSF has widespread clinical use in chemotherapy-induced neutropenia, severe chronic neutropenia, peripheral blood cell mobilization and bone marrow transplantation [31]. Previous studies have demonstrated a beneficial effect on the course of experimental infection with C.

Recently, we have shown that recombinant murine G-CSF also beneficially influences the course of potentially lethal acute disseminated candidiasis in non-neutropenic CBA mice [34]. Also, we were able to demonstrate that PMNs were mobilized by rG-CSF at the site of the infection and that their production of oxygen radicals was increased [34]. Histopathology showed extensive hyphal outgrowth of C.

In animals that had received a single dose of rG-CSF, the infectious foci were less numerous than in controls and the inflammatory infiltrates contained larger amounts of PMNs, with fewer yeasts present. In contrast to those in placebo-treated controls, Candida cells in the organs of rG-CSF-treated animals were almost completely limited to the yeast form and in most infiltrates, hyphae were absent [34].

Mice 10 animals per group were injected with a single dose of either or ng of rG-CSF or saline, 1 day before infection. Significant difference between controls and treatment groups: Mice were injected subcutaneous s. In subsequent studies, we have investigated whether rG-CSF is effective when given at later time points in models of subacute and less overwhelming disseminated candidiasis or when combined with anti-fungal drugs. In the model of rapidly lethal Candida infection, the effect of a single dose of rG-CSF was greatest when given 24 h before injection of C.

When treatment was postponed until 6 h after the onset of infection, the beneficial effect on the survival and organ load of Candida became less pronounced and if administration of rG-CSF was delayed until 24 h after injection of large amounts of C. Nevertheless, such a treatment, even when begun as late as after 24 h, had a notable impact on the histopathology at the sites of infection. A significantly reduced outgrowth of pseudohyphae as well as an enhanced influx of PMNs at the sites of infection was seen on microscopic examination in rG-CSF-treated mice, when compared with placebo-treated controls Fig.

Histopathology of the kidneys of mice 3 days after i. In control animals, infiltrates are numerous and consist of large amounts of C. Administration of rG-CSF as late as 24 h after infection resulted in a reduced outgrowth of pseudohyphae as well as an enhanced influx of PMNL at the sites of infection, as compared to control animals B. When more attenuated or sublethal types of disseminated Candida infection were studied, treatment with rG-CSF for up to 10 days had little effect. The outgrowth of C. This is in agreement with the observations of others, who described a beneficial effect on the survival of mice only when rG-CSF was either given in very high doses [35] or in combination therapy with anti-fungal drugs, but only when begun before or immediately after infection and only when small amounts of C.

Although the results of treatment of experimental candidiasis with rG-CSF are encouraging, it may be more clinically relevant to determine whether rG-CSF can augment anti-fungal drug treatment rather than stand on its own. As an anti-fungal drug, we selected fluconazole, because it has been shown to be the drug of choice for treatment of candidemia and disseminated infection with C. At 6 h after the onset of experimental disseminated candidiasis in non-neutropenic mice, treatment was started with either rG-CSF, fluconazole or both. In a potentially lethal model of disseminated candidiasis, the mortality was significantly reduced by treatment with rG-CSF alone, as well as by fluconazole in a dose-dependent fashion Fig.

Although combined therapy appeared not to have an additive effect on survival, the effect of both drugs was additive in inhibiting the fungal burden in the organs of infected mice. Organism Names see more details , Actinobacteridae actinobacteridae Subject Category: Organism Names see more details , Actinobacteria actinobacteria Subject Category: Organism Names see more details , Plasmodiidae plasmodiidae Subject Category: Organism Names see more details , Haemospororida haemospororida Subject Category: Organism Names see more details , Apicomplexa apicomplexa Subject Category: Organism Names see more details , Salmonella enterica subsp.

Organism Names see more details , Salmonella enterica salmonella enterica Subject Category: Organism Names see more details , Salmonella salmonella Subject Category: Organism Names see more details , Enterobacteriaceae enterobacteriaceae Subject Category: Organism Names see more details , Enterobacteriales enterobacteriales Subject Category: Organism Names see more details , Sarcocystidae sarcocystidae Subject Category: Organism Names see more details , Eucoccidiorida eucoccidiorida Subject Category: In line with our Privacy Policy, we want to make you aware about what we do with the information you provide when you create your My CABI account.

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Author Author Serial Subject. Previous record Next record. Actions Tools Choose a colour. Cytokines are discussed, in separate papers, in the context of virus infections, treatment of bacterial infections in neutropenic and non-neutropenic animals, intracellular Listeria monocytogenes and Salmonella typhimurium, legionellosis, mycobacterial infection, fungal infections, pathology and Kluwer Academic Publishers, Dordrecht, Netherlands.

Cytokines cytokines Subject Category: Chemicals and Chemical Groups see more details are discussed, in separate papers, in the context of virus infections, treatment treatment Subject Category: Techniques, Methodologies and Equipment see more details of bacterial infections in neutropenic and non-neutropenic animals animals Subject Category: Organism Names see more details , intracellular Listeria monocytogenes listeria monocytogenes Subject Category: Organism Names see more details and Salmonella typhimurium salmonella typhimurium Subject Category: Molecular Basis of Pulmonary Disease.

Ocular and Adnexal Lymphoma. Viral Infections of the Human Nervous System. Neurologic Complications of Cancer Therapy. The American Cancer Society. Bioterrorism and Infectious Agents. Lung Disease in Rheumatoid Arthritis. Fibrocystic Diseases of the Liver. Clinical and Basic Immunodermatology.

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Cytokines in the treatment of infectious diseases: options for the modulation of host defense.

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