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- Hellerud, B. C., et al.
(författare)
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Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis
- 2017
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Ingår i: Journal of Intensive Care. - : Springer Science and Business Media LLC. - 2052-0492. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis. Methods: Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated Neisseria meningitidis administered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group (n = 12) receiving saline and to an interventional group (n = 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin. Results: A substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group (p = 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-gamma by 75% (p = 0.0001), tumor necrosis factor by 50% (p = 0.01), Interleukin (IL)-8 by 50% (p = 0.03), IL-10 by 40% (p = 0.04), IL-12p40 by 50% (p = 0.03), and granulocyte CD11b (CR3) expression by 20% (p = 0.01). Conclusion: Inhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.
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| 2. |
- Gaarden, T. L., et al.
(författare)
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Exploration of 27 plasma immune markers: a cross-sectional comparison of 64 old psychiatric inpatients having unipolar major depression and 18 non-depressed old persons
- 2018
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Ingår i: BMC Geriatr. - : Springer Science and Business Media LLC. - 1471-2318. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalence of major depression (MD) according to population studies is the same for old (65 years and older) and younger adults. In contrast, an elevated proportion of old MD patients are hospitalized compared to younger adults with MD, indicating a need to expand the characteristics of old inpatients with MD. To illustrate this point, the association between inflammation and MD in old psychiatric inpatients is sparsely investigated even though an association between inflammation and treatment resistance among younger adults with MD has been reported. In this study, we aimed to explore the plasma concentrations of 27 immune markers in old inpatients with MD, and our purpose was to expand the understanding of inflammatory mechanisms in these patients. Methods: Prior to electroconvulsive treatment of MD, we compared 64 inpatients with unipolar MD (mean age 75.2 years) and 18 non-depressed controls (mean age 78.0 years). Symptoms characterizing MD were assessed by the Hamilton Rating Scale of Depression (HRSD)-17, and the immune markers from peripheral blood plasma were analysed using multiplex assay technology. For statistical analysis of data, we used the independent samples median test, independent samples t-test, chi(2)-test, receiver operating characteristic curve analyses, stepwise discriminant analysis, and multivariate linear regression. Results: Twenty-two immune markers representing pro-and anti-inflammatory, adaptive and trophic signalling had higher concentrations in the inpatients compared to the controls. Only the four immune markers IL-1 beta, IL-5, IL-10 and IL-15 had concentrations below the lower detection limit in a considerable portion (above 20%) of the patient cases. A combination of the concentration in plasma of TNF, vascular endothelial growth factor (VEGF), IL-1 beta, IL-7 and monocyte chemotactic protein (MCP)-1, correctly classified 98.4% of the depressed patients and 83.3% of the non-depressed controls. Plasma concentration of TNF and VEGF were associated with the HRSD-17 scores (p = 0.017 and 0.005, respectively). Conclusions: Our results indicate that several inflammatory mechanisms may be highly activated in old psychiatric inpatients with MD, and indicate that immune markers may contribute to a more comprehensive understanding of MD in old persons.
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| 5. |
- Otterdal, K, et al.
(författare)
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Rickettsia conorii is a potent complement activator in vivo and combined inhibition of complement and CD14 is required for attenuation of the cytokine response ex vivo.
- 2016
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Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 22:8, s. 734.e1-734.e6
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Tidskriftsartikel (refereegranskat)abstract
- Mediterranean spotted fever caused by Rickettsia conorii is a potentially lethal disease characterized by vascular inflammation affecting multiple organs. Studies of R. conorii so far have focused on activation of inflammatory cells and their release of inflammatory cytokines, but complement activation has not been investigated in R. conorii-infected patients. Here, we performed a comprehensive analysis of complement activation markers and the soluble cross-talking co-receptor CD14 (sCD14) in plasma from R. conorii-infected patients. The clinical data were supplemented with ex vivo experiments where the cytokine response was characterized in human whole blood stimulated with R. conorii. Complement activation markers at the level of C3 (C3bc, C3bBbP) and terminal pathway activation (sC5b-9), as well as sCD14, were markedly elevated (p <0.01 for all), and closely correlated (p <0.05 for all), in patients at admission compared with healthy matched controls. All tested markers were significantly reduced to baseline values at time of follow up. Rickettsia conorii incubated in human whole blood was shown to trigger complement activation accompanied by release of the inflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8 and tumour necrosis factor. Whereas inhibition of either C3 or CD14 had only a minor effect on released cytokines, combined inhibition of C3 and CD14 resulted in significant reduction, virtually to baseline levels, of the four cytokines (p <0.05 for all). Our data show that complement is markedly activated upon R. conorii infection and complement activation is, together with CD14, responsible for a major part of the cytokine response induced by R. conorii in human whole blood.
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| 8. |
- Hovland, Anders, et al.
(författare)
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The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis
- 2015
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Ingår i: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 241:2, s. 480-494
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Forskningsöversikt (refereegranskat)abstract
- Despite recent medical advances, atherosclerosis is a global burden accounting for numerous deaths and hospital admissions. Immune-mediated inflammation is a major component of the atherosclerotic process, but earlier research focus on adaptive immunity has gradually switched towards the role of innate immunity. The complement system and toll-like receptors (TLRs), and the crosstalk between them, may be of particular interest both with respect to pathogenesis and as therapeutic targets in atherosclerosis. Animal studies indicate that inhibition of C3a and C5a reduces atherosclerosis. In humans modified LDL-cholesterol activate complement and TLRs leading to downstream inflammation, and histopathological studies indicate that the innate immune system is present in atherosclerotic lesions. Moreover, clinical studies have demonstrated that both complement and TLRs are upregulated in atherosclerotic diseases, although interventional trials have this far been disappointing. However, based on recent research showing an intimate interplay between complement and TLRs we propose a model in which combined inhibition of both complement and TLRs may represent a potent anti-inflammatory therapeutic approach to reduce atherosclerosis. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
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