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Thomas, A. M., Gerogianni, A., McAdam, M. B., Floisand, Y., Lau, C., Espevik, T., . . . Barratt-Due, A. (2019). Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood. Journal of Immunology, 203(6), 1571-1578
Åpne denne publikasjonen i ny fane eller vindu >>Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood
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2019 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 203, nr 6, s. 1571-1578Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Heme is a critical danger molecule liberated from hemeproteins in various conditions, including from hemoglobin in hemolytic diseases. Heme may cause thromboinflammatory damage by activating inflammatory and hemostatic pathways, such as complement, the TLRs, coagulation, and platelets. In this study, we explored the effect of single and dual inhibition of complement component C5 and TLR coreceptor CD14 on heme-induced thromboinflammation in an ex vivo human whole blood model. Heme induced a dose-dependent activation of complement via the alternative pathway. Single inhibition of C5 by eculizumab attenuated the release of IL-6, IL-8, TNF, MCP-1, MIP-1 alpha, IFN-gamma, LTB-4, MMP-8 and -9, and IL-1Ra with more than 60% (p < 0.05 for all) reduced the upregulation of CD11b on granulocytes and monocytes by 59 and 40%, respectively (p < 0.05), and attenuated monocytic tissue factor expression by 33% (p < 0.001). Blocking CD14 attenuated IL-6 and TNF by more than 50% (p < 0.05). In contrast to single inhibition, combined C5 and CD14 was required for a significantly attenuated prothrombin cleavage (72%, p < 0.05). Markers of thromboinflammation were also quantified in two patients admitted to the hospital with sickle cell disease (SCD) crisis. Both SCD patients had pronounced hemolysis and depleted plasma hemopexin and haptoglobin. Plasma heme and complement activation was markedly increased in one patient, a coinciding observation as demonstrated ex vivo. In conclusion, heme-induced thromboinflammation was largely attenuated by C5 inhibition alone, with a beneficial effect of adding a CD14 inhibitor to attenuate prothrombin activation. Targeting C5 has the potential to reduce thromboinflammation in SCD crisis patients.

sted, utgiver, år, opplag, sider
American Association for Immunologists, 2019
HSV kategori
Forskningsprogram
Biomedicinsk vetenskap, Immunologi
Identifikatorer
urn:nbn:se:lnu:diva-89311 (URN)10.4049/jimmunol.1900047 (DOI)000484842100016 ()31413105 (PubMedID)
Tilgjengelig fra: 2019-09-26 Laget: 2019-09-26 Sist oppdatert: 2019-09-26bibliografisk kontrollert
Islam, M. M., Sharifi, R., Mamodaly, S., Islam, R., Nahra, D., Abusamra, D. B., . . . Gonzalez-Andrades, M. (2019). Effects of gamma radiation sterilization on the structural and biological properties of decellularized corneal xenografts. Acta Biomaterialia, 96, 330-344
Åpne denne publikasjonen i ny fane eller vindu >>Effects of gamma radiation sterilization on the structural and biological properties of decellularized corneal xenografts
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2019 (engelsk)Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 96, s. 330-344Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

To address the shortcomings associated with corneal transplants, substantial efforts have been focused on developing new modalities such as xenotransplantion. Xenogeneic corneas are anatomically and biomechanically similar to the human cornea, yet their applications require prior decellularization to remove the antigenic components to avoid rejection. In the context of bringing decellularized corneas into clinical use, sterilization is a crucial step that determines the success of the transplantation. Well-standardized sterilization methods, such as gamma irradiation (GI), have been applied to decellularized porcine corneas (DPC) to avoid graft-associated infections in human recipients. However, little is known about the effect of GI on decellularized corneal xenografts. Here, we evaluated the radiation effect on the ultrastructure, optical, mechanical and biological properties of DPC. Transmission electron microscopy revealed that gamma irradiated decellularized porcine cornea (G-DPC) preserved its structural integrity. Moreover, the radiation did not reduce the optical properties of the tissue. Neither DPC nor G-DPC led to further activation of complement system compared to native porcine cornea when exposed to plasma. Although, DPC were mechanically comparable to the native tissue, GI increased the mechanical strength, tissue hydrophobicity and resistance to enzymatic degradation. Despite these changes, human corneal epithelial, stromal, endothelial and hybrid neuroblastoma cells grew and differentiated on DPC and G-DPC. Thus, GI may achieve effective tissue sterilization without affecting critical properties that are essential for corneal transplant survival. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

sted, utgiver, år, opplag, sider
Elsevier, 2019
Emneord
Gamma irradiation sterilization, Decellularization, Corneal transplant, Recellularization, Acellular porcine cornea
HSV kategori
Forskningsprogram
Naturvetenskap, Medicin
Identifikatorer
urn:nbn:se:lnu:diva-89412 (URN)10.1016/j.actbio.2019.07.002 (DOI)000486132900027 ()31284096 (PubMedID)
Tilgjengelig fra: 2019-10-03 Laget: 2019-10-03 Sist oppdatert: 2019-10-03bibliografisk kontrollert
Shahini, N., Ueland, T., Auensen, A., Michelsen, A. E., Ludviksen, J. K., Hussain, A. I., . . . Louwe, M. C. (2019). Increased Complement Factor B and Bb Levels Are Associated with Mortality in Patients with Severe Aortic Stenosis. Journal of Immunology, 203(7), 1973-1980
Åpne denne publikasjonen i ny fane eller vindu >>Increased Complement Factor B and Bb Levels Are Associated with Mortality in Patients with Severe Aortic Stenosis
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2019 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 203, nr 7, s. 1973-1980Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, n = 123; population 2, n = 436; population 3, n = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; p = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.

sted, utgiver, år, opplag, sider
American Association of Immuologists, 2019
HSV kategori
Forskningsprogram
Biomedicinsk vetenskap, Immunologi
Identifikatorer
urn:nbn:se:lnu:diva-89529 (URN)10.4049/jimmunol.1801244 (DOI)000487578500028 ()31492744 (PubMedID)
Tilgjengelig fra: 2019-10-11 Laget: 2019-10-11 Sist oppdatert: 2019-10-11bibliografisk kontrollert
Thorgersen, E. B., Barratt-Due, A., Haugaa, H., Harboe, M., Pischke, S. E., Nilsson, P. H. & Mollnes, T. E. (2019). The Role of Complement in Liver Injury, Regeneration, and Transplantation. Hepatology, 70(2), 725-736
Åpne denne publikasjonen i ny fane eller vindu >>The Role of Complement in Liver Injury, Regeneration, and Transplantation
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2019 (engelsk)Inngår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 70, nr 2, s. 725-736Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double-edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia-reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2019
HSV kategori
Forskningsprogram
Naturvetenskap, Medicin
Identifikatorer
urn:nbn:se:lnu:diva-87059 (URN)10.1002/hep.30508 (DOI)000476407000001 ()30653682 (PubMedID)
Tilgjengelig fra: 2019-08-01 Laget: 2019-08-01 Sist oppdatert: 2019-10-11bibliografisk kontrollert
Thomas, A. M., Gerogianni, A., Barratt-Due, A., McAdam, M. B., Mollnes, T. E. & Nilsson, P. H. (2018). Complement (C5)-inhibition attenuates heme-induced inflammation in human whole blood. Paper presented at 27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, NM. Molecular Immunology, 102, 220-220
Åpne denne publikasjonen i ny fane eller vindu >>Complement (C5)-inhibition attenuates heme-induced inflammation in human whole blood
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2018 (engelsk)Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, s. 220-220Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
Elsevier, 2018
Emneord
Complement, Heme, Inflammation, Thromboinflammation, Complement 5
HSV kategori
Forskningsprogram
Biomedicinsk vetenskap, Immunologi
Identifikatorer
urn:nbn:se:lnu:diva-78411 (URN)10.1016/j.molimm.2018.06.228 (DOI)000445313600224 ()
Konferanse
27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, NM
Tilgjengelig fra: 2018-10-22 Laget: 2018-10-22 Sist oppdatert: 2018-11-16bibliografisk kontrollert
Orrem, H. L., Nilsson, P. H., Pischke, S. E., Kleveland, O., Yndestad, A., Ekholt, K., . . . Mollnes, T. E. (2018). IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction. Frontiers in Immunology, 9, Article ID 2035.
Åpne denne publikasjonen i ny fane eller vindu >>IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction
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2018 (engelsk)Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, artikkel-id 2035Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (> 50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

sted, utgiver, år, opplag, sider
Frontiers Media S.A., 2018
Emneord
complement, C5a receptors, C3a receptor, IL-6, myocardial infarction, inflammation
HSV kategori
Forskningsprogram
Biomedicinsk vetenskap, Immunologi
Identifikatorer
urn:nbn:se:lnu:diva-78097 (URN)10.3389/fimmu.2018.02035 (DOI)000444419300001 ()2-s2.0-85053134350 (Scopus ID)
Tilgjengelig fra: 2018-10-01 Laget: 2018-10-01 Sist oppdatert: 2019-08-29bibliografisk kontrollert
Mohlin, C., Petrus-Reurer, S., Lanner, F., Sandholm, K., Nilsson, P. H., Nilsson, B. & Nilsson Ekdahl, K. (2018). Is the polarized secretion of complement factor H of importance in age-related macular degeneration?. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI. Investigative Ophthalmology and Visual Science, 59(9)
Åpne denne publikasjonen i ny fane eller vindu >>Is the polarized secretion of complement factor H of importance in age-related macular degeneration?
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2018 (engelsk)Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, nr 9Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018
HSV kategori
Forskningsprogram
Naturvetenskap, Optometri
Identifikatorer
urn:nbn:se:lnu:diva-78425 (URN)000442932806149 ()
Konferanse
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI
Tilgjengelig fra: 2018-10-22 Laget: 2018-10-22 Sist oppdatert: 2018-11-16bibliografisk kontrollert
Orrem, H. L., Shetelig, C., Ueland, T., Limalanathan, S., Nilsson, P. H., Husebye, T., . . . Yndestad, A. (2018). Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction. International Journal of Cardiology, 268, 187-192
Åpne denne publikasjonen i ny fane eller vindu >>Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction
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2018 (engelsk)Inngår i: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 268, s. 187-192Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1 alpha and IL-1 beta are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling. Methods: Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n=65). Results: IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates. Conclusion: Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI. (C 18 Elsevier B.V. All rights reserved.

sted, utgiver, år, opplag, sider
Elsevier, 2018
Emneord
Inflammation, Cytokine, Interleukin-1, Acute coronary syndromes, Myocardial infarction, Ventricular remodelling
HSV kategori
Forskningsprogram
Naturvetenskap, Biomedicinsk vetenskap; Kemi, Biokemi
Identifikatorer
urn:nbn:se:lnu:diva-77369 (URN)10.1016/j.ijcard.2018.05.032 (DOI)000439363400045 ()29853279 (PubMedID)2-s2.0-85047477899 (Scopus ID)
Tilgjengelig fra: 2018-08-30 Laget: 2018-08-30 Sist oppdatert: 2019-08-29bibliografisk kontrollert
Wibroe, P. P., Anselmo, A. C., Nilsson, P. H., Sarode, A., Gupta, V., Urbanics, R., . . . Moghimi, S. M. (2017). Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.. Nature Nanotechnology, 12(6), 589-594
Åpne denne publikasjonen i ny fane eller vindu >>Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.
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2017 (engelsk)Inngår i: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 12, nr 6, s. 589-594Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2017
HSV kategori
Forskningsprogram
Biomedicinsk vetenskap, Immunologi
Identifikatorer
urn:nbn:se:lnu:diva-65207 (URN)10.1038/nnano.2017.47 (DOI)000402769100019 ()28396605 (PubMedID)2-s2.0-85017261848 (Scopus ID)
Tilgjengelig fra: 2017-06-12 Laget: 2017-06-12 Sist oppdatert: 2019-08-29bibliografisk kontrollert
Nilsson, P. H., Johnson, C., Pischke, S. E., Fure, H., Landsem, A., Bergseth, G., . . . Mollnes, T. E. (2017). Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation. Paper presented at 16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK. Molecular Immunology, 89, 136-137
Åpne denne publikasjonen i ny fane eller vindu >>Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation
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2017 (engelsk)Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, s. 136-137Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
HSV kategori
Forskningsprogram
Biomedicinsk vetenskap, Immunologi
Identifikatorer
urn:nbn:se:lnu:diva-68146 (URN)10.1016/j.molimm.2017.06.075 (DOI)000410014500056 ()
Konferanse
16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK
Tilgjengelig fra: 2017-10-02 Laget: 2017-10-02 Sist oppdatert: 2018-11-16bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-7192-5794