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  • 1.
    Barratt-Due, Andreas
    et al.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Pischke, Søren Erik
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway.
    Mollnes, Tom Eirik
    Norwegian University of Science and Technology, Norway ; Nordland Hospital, Norway ; University of Tromsø, Norway.
    Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets.2017In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 101, no 1, p. 193-204Article in journal (Refereed)
    Abstract [en]

    The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by "dual blockade" of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.

  • 2.
    Berg, Aase
    et al.
    Stavanger University Hospital, Norway ; University of Bergen, Norway.
    Otterdal, Kari
    Oslo University Hospital Rikshospitalet, Norway.
    Patel, Sam
    Central Hospital of Maputo, Mozambique.
    Gonca, Miguel
    Central Hospital of Maputo, Mozambique.
    David, Catarina
    Central Hospital of Maputo, Mozambique.
    Dalen, Ingvild
    Stavanger University Hospital, Norway.
    Nymo, Stig
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson, Margareta
    Oslo University Hospital Rikshospitalet, Norway.
    Nordling, Sofia
    Uppsala University.
    Magnusson, Peetra U
    Uppsala University.
    Ueland, Thor
    Oslo University Hospital Rikshospitalet, Norway.
    Prato, Mauro
    University of Torino, Italy.
    Giribaldi, Giuliana
    University of Torino, Italy.
    Mollnes, Tom Eirik
    Oslo University Hospital Rikshospitalet, Norway.
    Aukrust, Pål
    Oslo University Hospital Rikshospitalet, Norway.
    Langeland, Nina
    University of Bergen, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria.2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 11, p. 1835-1840Article in journal (Refereed)
    Abstract [en]

    The impact of complement activation and its possible relation to cytokine responses during malaria pathology was investigated in plasma samples from patients with confirmed Plasmodium falciparum malaria and in human whole-blood specimens stimulated with malaria-relevant agents ex vivo. Complement was significantly activated in the malaria cohort, compared with healthy controls, and was positively correlated with disease severity and with certain cytokines, in particular interleukin 8 (IL-8)/CXCL8. This was confirmed in ex vivo-stimulated blood specimens, in which complement inhibition significantly reduced IL-8/CXCL8 release. P. falciparum malaria is associated with systemic complement activation and complement-dependent release of inflammatory cytokines, of which IL-8/CXCL8 is particularly prominent.

  • 3.
    Bergseth, Grethe
    et al.
    Nordland Hospital, Bodø, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway.
    Thomas, Anub Mathew
    Radboud University Medical Center, The Netherlands.
    Gustavsen, Alice
    University of Oslo, Rikshospitalet, Norway.
    Volokhina, Elena B
    Radboud University Medical Center, The Netherlands.
    van den Heuvel, Lambertus P
    Radboud University Medical Center, The Netherlands.
    Barratt-Due, Andreas
    University of Oslo, Rikshospitalet, Norway.
    Mollnes, Tom E
    University of Oslo, Rikshospitalet, Norway;Nordland Hospital, Norway;University of Tromsø, Norway.
    Neoepitope based assays to detect C5a – Pitfalls and interpretations2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 201-201Article in journal (Refereed)
  • 4.
    Ehrnthaller, Christian
    et al.
    University of Ulm, Germany.
    Huber-Lang, Markus
    University of Ulm, Germany.
    Nilsson, Per H.
    University of Oslo, Norway.
    Bindl, Ronny
    University of Ulm, Germany.
    Redeker, Simon
    University of Ulm, Germany.
    Recknagel, Stefan
    University of Ulm, Germany.
    Rapp, Anna
    University of Ulm, Germany.
    Mollnes, Tom
    University of Oslo, Norway.
    Amling, Michael
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Gebhard, Florian
    University of Ulm, Germany.
    Ignatius, Anita
    University of Ulm, Germany.
    Complement C3 and C5 deficiency affects fracture healing.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, article id UNSP e81341Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence that complement may play a role in bone development. Our previous studies demonstrated that the key complement receptor C5aR was strongly expressed in the fracture callus not only by immune cells but also by bone cells and chondroblasts, indicating a function in bone repair. To further elucidate the role of complement in bone healing, this study investigated fracture healing in mice in the absence of the key complement molecules C3 and C5. C3(-/-) and C5(-/-) as well as the corresponding wildtype mice received a standardized femur osteotomy, which was stabilized using an external fixator. Fracture healing was investigated after 7 and 21 days using histological, micro-computed tomography and biomechanical measurements. In the early phase of fracture healing, reduced callus area (C3(-/-): -25%, p=0.02; C5(-/-): -20% p=0.052) and newly formed bone (C3(-/-): -38%, p=0.01; C5(-/-): -52%, p=0.009) was found in both C3- and C5-deficient mice. After 21 days, healing was successful in the absence of C3, whereas in C5-deficient mice fracture repair was significantly reduced, which was confirmed by a reduced bending stiffness (-45%; p=0.029) and a smaller callus volume (-17%; p=0.039). We further demonstrated that C5a was activated in C3(-/-) mice, suggesting cleavage via extrinsic pathways. Our results suggest that the activation of the terminal complement cascade in particular may be crucial for successful fracture healing.

  • 5.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Region Skåne.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Fromell, Karin
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Univ Tromsö, Norway.
    Rosengren-Holmberg, Jenny P.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Swedish Natl Lab Forens Sci, Linköping.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 36, p. 55-65Article in journal (Refereed)
    Abstract [en]

    Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. (C) 2014 Elsevier Ltd. All rights reserved.

  • 6.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mollnes, Tom Eirik
    Rosengren-Holmberg, Jenny P.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    The ratio between C4 and C4BP adsorbed from plasma predicts cytokine generation induced by artificial polymers in contact with whole blood2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1211-1211Article in journal (Other academic)
  • 7.
    Engberg, Anna E.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Rikshosp, Univ Hosp, Norway.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mollnes, T. E.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala university.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university.
    The ratio between C4 and C4BP adsorbed to artificial materials is a new predictor for biocompatibility2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3, p. 309-309Article in journal (Other academic)
  • 8.
    Engberg, Anna E.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren-Holmberg, Jenny P
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nilsson, Per H.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bäck,
    Department of Oncology, Radiology and Clinical Immunology, Section of Clinical Immunology, Rudbeck Laboratory C5, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
    Mollnes, Tom Eirik
    Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway,Research Laboratory, Nordland Hospital, Bodø, and University of Tromsø, Norway.
    Nicholls, Ian A.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nilsson, Bo
    Department of Oncology, Radiology and Clinical Immunology, Section of Clinical Immunology, Rudbeck Laboratory C5, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    EVALUATION OF THE HEMOCOMPATIBILITY OF NOVEL POLYMERIC MATERIALSManuscript (preprint) (Other academic)
    Abstract [en]

    When a biomaterial surface comes in contact with blood an immediate adsorption of plasma proteins to the surface will occur, and the cascade systems in the blood, such as the complement, coagulation and contact system, will be activated to various degrees. The intensity of this reaction will determine the hemocompatibility of the materials. Here we present an evaluation of the link between the composition, the physico-chemical properties and the protein adsorption properties of six newly synthesized polymers (P1-P6) and the hemocompatibility.The hemocompatibility of the polymeric surfaces was evaluated in human blood plasma and whole blood. Commercially available polyvinylchloride (PVC) was used as reference material. The hemocompatibility of the polymeric surfaces was evaluated with regard to complement activation (C3a and sC5-9 generation) and coagulation activation (platelet loss and TAT-formation) and cytokine productions (27 analytes in multiplex assay) after contact with whole blood. Contact activation was quantified by analyses of FXIIa-C1INH, FXIa-C1INH, and kallikrein-C1INH complexes.Polymers P2 (p<0.05 for C3a), P3, P5 and P6 showed less complement activation, and polymers P1 and P4 (p<0.05 for platelet loss), as well as P5 and P6 showed less coagulation activation compared with reference PVC. Polymers P1-P3 induced activation of the contact system, P3 being the most potent. Secretion of 17 cytokines including chemokines and growth factors were differentially influenced by the polymers, P1 and P3 being significantly (p<0.05) more compatible for five of the analytes.Collectively these data demonstrate that the composition of the polymers clearly leads to different biological properties as a consequence of distinctive physico-chemical properties and protein adsorption patterns.1

  • 9.
    Fretland, Asmund Avdem
    et al.
    The Intervention Centre, Oslo University Hospital, Norway.
    Sokolov, Andrey
    Oslo University Hospital, Norway.
    Postriganova, Nadya
    Intervention Centre, Oslo University Hospital, Norway.
    Kazaryan, Airazat M
    Intervention Centre, Oslo University Hospital, Norway.
    Pischke, Soren E
    Intervention Centre, Oslo University Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway.
    Rognes, Ingrid Nygren
    Oslo University Hospital, Norway.
    Bjornbeth, Bjorn Atle
    Oslo University Hospital, Norway.
    Fagerland, Morten Wang
    Oslo University Hospital, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway.
    Edwin, Bjorn
    Intervention Centre, Oslo University Hospital, Norway.
    Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial.2015In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 94, no 42, p. 1-7, article id e1786Article in journal (Refereed)
    Abstract [en]

    Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial.This was a predefined exploratory substudy within the Oslo CoMet-study. Forty-five patients with CLM were randomized to laparoscopic (n = 23) or open (n = 22) resection. Ethylenediaminetetraacetic acid-plasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at -80 C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cell-free DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation.Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1β, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, C-reactive protein, and macrophage inflammatory protein -1β, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.Laparoscopic resection of CLM reduced the inflammatory response compared with open resection. The lower level of HMGB-1 is interesting because of the known association with oncogenesis.

  • 10. Hamad, Osama A
    et al.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nilsson, Per H.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Andersson, Jonas
    Magotti, Paola
    Lambris, John D
    Nilsson, Bo
    Complement activation triggered by chondroitin sulfate reelased by thrombin receptor-activated platelets2008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 8, p. 1413-1421Article in journal (Refereed)
  • 11.
    Hamad, Osama A.
    et al.
    Uppsala University.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lasaosa, Maria
    University of Pennsylvania, USA.
    Ricklin, Daniel
    University of Pennsylvania, USA.
    Lambris, John D.
    University of Pennsylvania, USA.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Contribution of Chondroitin Sulfate A to the Binding of Complement Proteins to Activated Platelets2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 9, article id e12889Article in journal (Refereed)
    Abstract [en]

    Background: Exposure of chondroitin sulfate A (CS-A) on the surface of activated platelets is well established. The aim of the present study was to investigate to what extent CS-A contributes to the binding of the complement recognition molecule C1q and the complement regulators C1 inhibitor (C1INH), C4b-binding protein (C4BP), and factor H to platelets.Principal Findings: Human blood serum was passed over Sepharose conjugated with CS-A, and CS-A-specific binding proteins were identified by Western blotting and mass spectrometric analysis. C1q was shown to be the main protein that specifically bound to CS-A, but C4BP and factor H were also shown to interact. Binding of C1INH was dependent of the presence of C1q and then not bound to CS-A from C1q-depleted serum. The specific interactions observed of these proteins with CS-A were subsequently confirmed by surface plasmon resonance analysis using purified proteins. Importantly, C1q, C4BP, and factor H were also shown to bind to activated platelets and this interaction was inhibited by a CS-A-specific monoclonal antibody, thereby linking the binding of C1q, C4BP, and factor H to exposure of CS-A on activated platelets. CS-A-bound C1q was also shown to amplify the binding of model immune complexes to both microtiter plate-bound CS-A and to activated platelets.

    Conclusions: This study supports the concept that CS-A contributes to the binding of C1q, C4BP, and factor H to platelets, thereby adding CS-A to the previously reported binding sites for these proteins on the platelet surface. CS-A-bound C1q also seems to amplify the binding of immune complexes to activated platelets, suggesting a role for this molecule in immune complex diseases. 

  • 12.
    Hamad, Osama
    et al.
    Uppsala University.
    Bäck, Jennie
    Uppsala University.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Platelets, Complement, and Contact Activation: Partners in inflammation and thrombosis2012In: Current Topics in Innate Immunity II / [ed] John D. Lambris &George Hajishengallis, Springer, 2012, Vol. 946, no Current Topics in Innate Immunity II. J. D. Lambris, G. Hajishengallis (eds.), p. 185-205Conference paper (Refereed)
    Abstract [en]

    Platelet activation during thrombotic events is closely associated with complement and contact system activation, which in turn leads to inflammation . Here we review the interactions between activated platelets and the complement and contact activation systems in clotting blood. Chondroitin sulfate A (CS-A), released from alpha granules during platelet activation, is a potent mediator of crosstalk between platelets and the complement system. CS-A activates complement in the fluid phase, generating anaphylatoxins that mediate leukocyte activation. No complement activation seems to occur on the activated platelet surface, but C3 in the form of C3(H2O) is bound to the surfaces of activated platelets . This finding is consistent with the strong expression of membrane-bound complement regulators present at the platelet surface. CS-A exposed on the activated platelets is to a certain amount responsible for recruiting soluble regulators to the surface. Platelet-bound C3(H2O) acts as a ligand for leukocyte CR1 (CD35), potentially enabling platelet–leukocyte interactions. In addition, platelet activation leads to the activation of contact system enzymes, which are specifically inhibited by antithrombin, rather than by C1INH, as is the case when contact activation is induced by material surfaces. Thus, in addition to their traditional role as initiators of secondary hemostasis, platelets also act as mediators and regulators of inflammation in thrombotic events.

  • 13.
    Hamad, Osama
    et al.
    Rudbeck Laboratory, University hospital, Uppsala.
    Nilsson, Per H.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Lambris, John D.
    University of Pennsylvania, USA.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences. Rudbeck Laboratory, University hospital, Uppsala.
    Nilsson, Bo
    Rudbeck Laboratory, University hospital, Uppsala.
    Binding of complement proteins to activated platelets is independent of complement activation2009In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 14, p. 2853-2853, article id OP95Article in journal (Refereed)
  • 14. Hamad, Osama
    et al.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Wouters, Diana
    Lambris, John
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Complement Component C3 Binds to Activated Normal Platelets without Preceding Proteolytic Activation and Promotes Binding to Complement Receptor 12010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 5, p. 2686-2692Article in journal (Refereed)
    Abstract [en]

    It has been reported that complement is activated on the surface of activated platelets, despite the presence of multiple regulators of complement activation. To reinvestigate the mechanisms by which activated platelets bind to complement components, the presence of complement proteins on the surfaces of nonactivated and thrombin receptor-activating peptide-activated platelets was analyzed by flow cytometry and Western blot analyses. C1q, C4, C3, and C9 were found to bind to thrombin receptor-activating peptide-activated platelets in lepirudin-anticoagulated platelet-rich plasma (PRP) and whole blood. However, inhibiting complement activation at the C1q or C3 level did not block the binding of C3 to activated platelets. Diluting PRP and chelating divalent cations also had no effect, further indicating that the deposition of complement components was independent of complement activation. Furthermore, washed, activated platelets bound added C1q and C3 to the same extent as platelets in PRP. The use of mAbs against different forms of C3 demonstrated that the bound C3 consisted of C3(H2O). Furthermore, exogenously added soluble complement receptor 1 was shown to bind to this form of platelet-bound C3. These observations indicate that there is no complement activation on the surface of platelets under physiological conditions. This situation is in direct contrast to a number of pathological conditions in which regulators of complement activation are lacking and thrombocytopenia and thrombotic disease are the ultimate result. However, the generation of C3(H2O) represents nonproteolytic activation of C3 and after factor I cleavage may act as a ligand for receptor binding.

  • 15.
    Harboe, M.
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Johnson, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nymo, S.
    Nordland Hospital, Norway.
    Ekholt, K.
    Oslo University Hospital Rikshospitalet, Norway.
    Schjalm, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Lindstad, J. K.
    Oslo University Hospital Rikshospitalet, Norway.
    Pharo, A.
    Oslo University Hospital Rikshospitalet, Norway.
    Hellerud, B. C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Mollnes, T. E.
    Oslo University Hospital Rikshospitalet, Norway ; Nordland Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Molecular modelling showed optimal fit between TSR5 in trimeric properdin and C345C in the C3b moiety for stabilization of the alternative convertase, whereas binding to molecular patterns in myeloperoxidase, endothelial cells and Neisseria meningitides was indirectly mediated by initial C3 activation2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1205-1205Article in journal (Refereed)
  • 16.
    Harboe, M.
    et al.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Johnson, C.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Lindstad, J. K.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Pharo, A.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Hellerud, B. C.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Nymo, S.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway ; University of Tromsö, Norway.
    Mollnes, T. E.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway ; University of Tromsö, Norway.
    Binding of properdin to myeloperoxidase and Neisseria meningitidis is C3-dependent2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, Special Issue, p. 142-142, article id 067Article in journal (Refereed)
  • 17.
    Harboe, Morten
    et al.
    Oslo University Hospital, Norway.
    Johnson, Christina
    Oslo University Hospital, Norway.
    Nymo, Stig
    Nordland Hospital, Norway.
    Ekholt, Karin
    Oslo University Hospital, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Norway.
    Lindstad, Julie K.
    Oslo University Hospital, Norway.
    Pharo, Anne
    Oslo University Hospital, Norway.
    Hellerud, Bernt Christian
    Oslo University Hospital, Norway.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway ; Nordland Hospital, Norway ; University of Oslo, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo University Hospital, Norway ; University of Oslo, Norway.
    Properdin binding to complement activating surfaces depends on initial C3b deposition2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 4, p. E534-E539Article in journal (Refereed)
    Abstract [en]

    Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

  • 18.
    Huang, Shan
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Elmlund, Louise
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Regulation of complement in whole blood by heparin molecularly imprinted polymer particles2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1199-1199Article in journal (Other academic)
  • 19.
    Huber-Lang, Markus
    et al.
    University of Ulm, Germany.
    Barratt-Due, Andreas
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Pischke, Søren E
    University of Oslo, Rikshospitalet, Norway.
    Sandanger, Øystein
    University of Oslo, Rikshospitalet, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway.
    Nunn, Miles A
    Ctr Ecol & Hydrol, Oxon, UK.
    Denk, Stephanie
    University of Ulm, Germany.
    Gaus, Wilhelm
    University of Ulm, Germany.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Mollnes, Tom E
    University of Oslo, Rikshospitalet, Norway ; Norwegian Univ Sci & Technol, Norway; University of Tromsö, Norway.
    Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice.2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 192, no 11, p. 5324-5331Article in journal (Refereed)
    Abstract [en]

    Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.

  • 20.
    Mahmoudi, Maryam
    et al.
    Teheran University of Medical Sciences, Iran.
    Nilsson, Per H.
    University of Oslo, Norway ; Oslo University Hospital, Rikshospitalet, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital, Rikshospitalet, Norway ; University of Oslo, Norway ; Nordland Hospital, Norway.
    Roos, Dirk
    University of Amsterdam, The Netherlands.
    Sullivan, Kathleen E.
    University of Pennsylvania, USA.
    Complement Deficiencies2017In: Primary Immunodeficiency Diseases: Definition, Diagnosis, and Management / [ed] Rezaei, Nima; Aghamohammadi, Asghar; Notarangelo, Luigi D, Berlin, Heidelberg: Springer, 2017, 2nd, p. 437-460Chapter in book (Refereed)
  • 21.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Petrus-Reurer, Sandra
    Karolinska Institutet;Karolinska University Hospital.
    Lanner, Fredrik
    Karolinska Institutet;Karolinska University Hospital.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Is the polarized secretion of complement factor H of importance in age-related macular degeneration?2018In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 9Article in journal (Other academic)
  • 22.
    Mollnes, T.
    et al.
    University of Oslo, Norway.
    Baratt-Due, A.
    University of Oslo, Norway.
    Pischke, S.
    Oslo University Hospital, Norway.
    Sandanger, I.
    Oslo University Hospital, Norway.
    Nilsson, Per H.
    University of Oslo, Norway.
    Lambris, J.
    University of Philadelphia, USA.
    Nunn, M.
    Centre for Ecology and Hydrology, Oxford, UK.
    Denk, S.
    University of Ulm, Germany.
    Espevik, T.
    Norwegian University of Science and Technology, Norway.
    Huber-Lang, M.
    University of Ulm, Germany.
    Double-blockade of CD14 and complement component C5 abolish the inflammatory storm and improve survival in mouse polymicrobial sepsis2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3, p. 294-294Article in journal (Refereed)
  • 23.
    Mollnes, Tom E
    et al.
    University of Oslo, Rikshospitalet, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Rikshospitalet, Norway.
    Letter to the Editor.2013In: Journal of clinical biochemistry and nutrition, ISSN 0912-0009, E-ISSN 1880-5086, Vol. 52, no 3, p. 253-254Article in journal (Refereed)
  • 24.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lambris, JD
    Elwing, H
    Ricklin, D
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Teramura, Y
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Innate immunity activation on biomaterial surfaces: A mechanistic model and coping strategies2011In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 63, no 12, p. 1042-1050Article, review/survey (Refereed)
    Abstract [en]

    When an artificial biomaterial (e.g., a stent or implantable pump) is exposed to blood, plasma proteins immediately adhere to the surface, creating a new interface between the biomaterial and the blood. The recognition proteins within the complement and contact activation/coagulation cascade systems of the blood will be bound to, or inserted into, this protein film and generate different mediators that will activate polymorphonuclear leukocytes and monocytes, as well as platelets. Under clinical conditions, the ultimate outcome of these processes may be thrombotic and inflammatory reactions, and consequently the composition and conformation of the proteins in the initial layer formed on the surface will to a large extent determine the outcome of a treatment involving the biomaterial, affecting both the functionality of the material and the patient's life quality. This review presents models of biomaterial-induced activation processes and describes various strategies to attenuate potential adverse reactions by conjugating bioactive molecules to surfaces or by introducing nanostructures.

  • 25.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Interactions between platelets and complement with implications for the regulation at surfaces2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Disturbances of host integrity have the potential to evoke activation of innate immunologic and hemostatic protection mechanisms in blood. Irrespective of whether the activating stimulus is typically immunogenic or thrombotic, it will generally affect both the complement system and platelets to a certain degree. The theme of this thesis is complement and platelet activity, which is intersected in all five included papers. The initial aim was to study the responses and mechanisms of the complement cascade in relation to platelet activation. The secondary aim was to use an applied approach to regulate platelets and complement on model biomaterial and cell surfaces.   

    Complement activation was found in the fluid phase in response to platelet activation in whole blood. The mechanism was traced to platelet release of stored chondroitin sulfate-A (CS-A) and classical pathway activation via C1q. C3 was detected at the platelet surface, though its binding was independent of complement activation. The inhibitors factor H and C4-binding protein (C4BP) were detected on activated platelets, and their binding was partly dependent on surface-exposed CS-A. Collectively, these results showed that platelet activation induces inflammatory complement activation in the fluid phase. CS-A was shown to be a central molecule in the complement-modulatory functions of platelets by its interaction with C1q, C4BP, and factor H.

    Platelet activation and surface adherence were successfully attenuated by conjugating an ADP-degrading apyrase on a model biomaterial. Only minor complement regulation was seen, and was therefore targeted specifically on surfaces and cells by co-immobilizing a factor H-binding peptide together with the apyrase. This combined approach led to a synchronized inhibition of both platelet and complement activation at the interface of biomaterials/xenogeneic cells and blood.

    In conclusion, here presents a novel crosstalk-mechanism for activation of complement when triggering platelets, which highlights the importance of regulating both complement and platelets to lower inflammatory events. In addition, a strategy to enhance the biocompatibility of biomaterials and cells by simultaneously targeting ADP-dependent platelet activation and the alternative complement C3-convertase is proposed.

  • 26.
    Nilsson, Per H.
    et al.
    University of Oslo, Rikshospitalet, Norway.
    Berg, A.
    e, Stavanger University Hospital, Norway ; Hospital of Maputo, Mozambique ; University of Bergen, Norway.
    Otterdal, K.
    University of Oslo, Rikshospitalet, Norway.
    Patel, S.
    Hospital of Maputo, Mozambique.
    Gonca, M.
    Hospital of Maputo, Mozambique.
    David, C.
    Hospital of Maputo, Mozambique.
    Dalen, I.
    Stavanger University Hospital, , Norway.
    Nymo, S.
    University of Oslo, Rikshospitalet, Norway ; Research Laboratory Nordland Hospital, Norway ; University of Tromsø, Norway.
    Nilsson, M.
    University of Oslo, Rikshospitalet, Norway.
    Ueland, T.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Prato, M.
    University of Torino Medical School, Italy.
    Giribaldi, G.
    University of Torino Medical School, Italy.
    Aukrust, P.
    University of Oslo, Rikshospitalet, Norway.
    Langeland, N.
    University of Bergen, Norway.
    Mollnes, T. E.
    University of Oslo, Rikshospitalet, Norway.
    Complement-dependent inflammatory response Plasmodium-derived hemozoin in malaria2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 230-230Article in journal (Refereed)
  • 27.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Engberg, Anna E.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Bäck, Jennie
    Div. Clinical Immunology, Rudbeck Laboratory, University Hospital, Uppsala.
    Faxälv, Lars
    Department of Clinical Chemistry, Laboratory Medicine, University Hospital, Linköping.
    Lindahl, Tomas
    Department of Clinical Chemistry, Laboratory Medicine, University Hospital, Linköping.
    Nilsson, Bo
    Div. Clinical Immunology, Rudbeck Laboratory, University Hospital, Uppsala.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    The creation of an antithrombotic surface by apyrase immobilization2010In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 16, p. 4484-4491Article in journal (Refereed)
    Abstract [en]

    Blood incompatibility reactions caused by surfaces often involve platelet activation and subsequent platelet-initiated activation of the coagulation and complement cascades. The goal of this study was to immobilize apyrase on a biomaterial surface in order to develop an enzymatically active surface that would have the capacity to inhibit platelet activation by degrading ADP. We were able to immobilize apyrase on a polystyrene surface with preservation of the enzymatic activity. We then analyzed the hemocompatibility of the apyrase surface and of control surfaces by incubation with platelet-rich plasma (PRP) or whole blood. Monitoring of markers of platelet, coagulation, and complement activation and staining of the surfaces revealed decreased levels of platelet and coagulation activation parameters on the apyrase surface. The formation of antithrombin-thrombin and antithrombin-factor XIa complexes and the extent of platelet consumption were significantly lower on the apyrase surface than on any of the control surfaces. No significant differences were seen in complement activation (C3a levels). Staining of the apyrase surface revealed low platelet adherence and no formation of granulocyte platelet complexes. These results demonstrate that it is possible to create an antithrombotic surface targeting the ADP amplification of platelet activation by immobilizing apyrase.

  • 28.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Johnson, Christina
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Fure, Hilde
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Landsem, Anne
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Haugaard-Kedström, Linda M.
    Univ Copenhagen, Denmark.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Brekke, Ole-Lars
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 136-137Article in journal (Other academic)
  • 29.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Rikshospitalet.
    Johnson, Christina
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Pischke, Søren E
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Fure, Hilde
    Nordland Hospital, Norway;University of Tromsø, Norway.
    Landsem, Anne
    Nordland Hospital, Norway;University of Tromsø, Norway.
    Bergseth, Grethe
    Nordland Hospital, Norway;University of Tromsø, Norway.
    Haugaard-Kedstrom, Linda M
    University of Copenhagen, Denmark.
    Huber-Lang, Markus
    University Hospital of Ulm, Germany.
    Brekke, Ole-Lars
    Nordland Hospital, Norway;University of Tromsø, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway;University of Oslo, Norway;Nordland Hospital, Norway;University of Tromsø, Norway.
    Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 136-137Article in journal (Refereed)
  • 30.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Magnusson, Peetra U
    Uppsala University.
    Qu, Hongchang
    University of Pennsylvania, USA.
    Iwata, Hiroo
    Kyoto University, Japan.
    Ricklin, Daniel
    University of Pennsylvania, USA.
    Hong, Jaan
    Uppsala University.
    Lambris, John D
    University of Pennsylvania, USA.
    Nilsson, Bo
    Uppsala University.
    Teramura, Yuji
    Uppsala University;Kyoto University, Japan.
    Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 4, p. 985-994Article in journal (Refereed)
    Abstract [en]

    Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor H-binding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.

  • 31.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Thomas, Anub Mathew
    Oslo Univ Hosp, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway.
    Gustavsen, Alice
    Oslo Univ Hosp, Norway.
    Volokhina, Elena B.
    Radboud Univ Nijmegen, Netherlands;Radboud Univ Nijmegen, Netherlands.
    van den Heuvel, Lambertus P.
    Radboud Univ Nijmegen, Netherlands;Univ Hosp Leuven, Belgium.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway.
    Mollnes, Tom E.
    Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 111-114Article in journal (Refereed)
    Abstract [en]

    The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.

  • 32.
    Nymo, Stig
    et al.
    Nordland Hospital, Norway ; University of Tromsø, Norway ; University of Oslo, Rikshospitalet, Norway.
    Gustavsen, Alice
    University of Oslo, Rikshospitalet, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Lau, Corinna
    Nordland Hospital, Norway ; University of Tromsø, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway ; Norwegian University of Science and Technology, Norway.
    Mollnes, Tom E.
    Nordland Hospital, Norway ; University of Tromsø, Norway ; University of Oslo, Rikshospitalet, Norway.
    Human Endothelial Cell Activation by Escherichia coli and Staphylococcus aureus Is Mediated by TNF and IL-1 beta Secondarily to Activation of C5 and CD14 in Whole Blood2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 5, p. 2293-2299Article in journal (Refereed)
    Abstract [en]

    Endothelial cells (EC) play a central role in inflammation. E-selectin and ICAM-1 expression are essential for leukocyte recruitment and are good markers of EC activation. Most studies of EC activation are done in vitro using isolated mediators. The aim of the present study was to examine the relative importance of pattern recognition systems and downstream mediators in bacteria-induced EC activation in a physiological relevant human model, using EC incubated with whole blood. HUVEC were incubated with human whole blood. Escherichia coli-and Staphylococcus aureus-induced EC activation was measured by E-selectin and ICAM-1 expression using flow cytometry. The mAb 18D11 was used to neutralize CD14, and the lipid A analog eritoran was used to block TLR4/MD2. C5 cleavage was inhibited using eculizumab, and C5aR1 was blocked by an antagonist. Infliximab and canakinumab were used to neutralize TNF and IL-1 beta. The EC were minimally activated when bacteria were incubated in serum, whereas a substantial EC activation was seen when the bacteria were incubated in whole blood. E. coli-induced activation was largely CD14-dependent, whereas S. aureus mainly caused a C5aR1-mediated response. Combined CD14 and C5 inhibition reduced E-selectin and ICAM-1 expression by 96 and 98% for E. coli and by 70 and 75% for S. aureus. Finally, the EC activation by both bacteria was completely abolished by combined inhibition of TNF and IL-1 beta. E. coli and S. aureus activated EC in a CD14- and C5-dependent manner with subsequent leukocyte secretion of TNF and IL-1 beta mediating the effect.

  • 33.
    Orrem, H. L.
    et al.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Barratt-Due, A.
    Oslo University Hospital, Norway.
    Pische, S. E.
    Oslo University Hospital, Norway.
    Grindheim, G.
    Rikshospitalet, Oslo University Hospital, Norway.
    Garred, P.
    University of Copenhagen, Denmark.
    Husebye, T.
    Oslo University Hospital Ullevål, Norway ; University of Oslo, Norway.
    Andersen, G. O.
    Oslo University Hospital Ullevål, Norway ; University of Oslo, Norway.
    Mollnes, T. E.
    Oslo University Hospital, Norway ; University of Oslo, Norway ; Research Laboratory Nordland Hospital, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Complement activation in acute heart failure following myocardial infarction2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1203-1204Article in journal (Refereed)
  • 34.
    Orrem, Hilde L.
    et al.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Natl Hosp Norway, Norway;Univ Oslo, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Kleveland, Ola
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Yndestad, Arne
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Ekholt, Karin
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Damas, Jan K.
    Norwegian Univ Sci & Technol, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Bendz, Bjorn
    Natl Hosp Norway, Norway.
    Halvorsen, Bente
    Univ Oslo, Norway;Natl Hosp Norway, Norway.
    Gregersen, Ida
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Wiseth, Rune
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Andersen, Geir O.
    Oslo Univ Hosp, Norway.
    Ueland, Thor
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Gullestad, Lars
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Natl Hosp Norway, Norway.
    Aukrust, Pal
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Barratt-Due, Andreas
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Mollnes, Tom E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway;Univ Tromso, Norway.
    IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2035Article in journal (Refereed)
    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.

  • 35.
    Orrem, Hilde L
    et al.
    Oslo University Hospital, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Norway;Oslo University Hospital, Rikshospitalet, Norway.
    Pischke, Søren E
    Oslo University Hospital, Rikshospitalet, Norway.
    Grindheim, Guro
    Oslo University Hospital, Rikshospitalet, Norway.
    Garred, Peter
    University of Copenhagen, Denmark.
    Seljeflot, Ingebjørg
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Husebye, Trygve
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Aukrust, Pål
    University of Oslo, Norway;Oslo University Hospital, Norway.
    Yndestad, Arne
    University of Oslo, Norway;Oslo University Hospital, Norway.
    Andersen, Geir Ø
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Barratt-Due, Andreas
    Oslo University Hospital, Rikshospitalet, Norway.
    Mollnes, Tom E
    Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway;University of Tromsø, Norway;Norwegian University of Science and Technology, Norway.
    Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock.2018In: ESC Heart Failure, E-ISSN 2055-5822, Vol. 5, no 3, p. 292-301Article in journal (Refereed)
    Abstract [en]

    AIMS: Heart failure (HF) is an impending complication to myocardial infarction. We hypothesized that the degree of complement activation reflects severity of HF following acute myocardial infarction.

    METHODS AND RESULTS: The LEAF trial (LEvosimendan in Acute heart Failure following myocardial infarction) evaluating 61 patients developing HF within 48 h after percutaneous coronary intervention-treated ST-elevation myocardial infarction herein underwent a post hoc analysis. Blood samples were drawn from inclusion to Day 5 and at 42 day follow-up, and biomarkers were measured with enzyme immunoassays. Regional myocardial contractility was measured by echocardiography as wall motion score index (WMSI). The cardiogenic shock group (n = 9) was compared with the non-shock group (n = 52). Controls (n = 44) were age-matched and sex-matched healthy individuals. C4bc, C3bc, C3bBbP, and sC5b-9 were elevated in patients at inclusion compared with controls (P < 0.01). The shock group had higher levels compared with the non-shock group for all activation products except C3bBbP (P < 0.05). At Day 42, all products were higher in the shock group (P < 0.05). In the shock group, sC5b-9 correlated significantly with WMSI at baseline (r = 0.68; P = 0.045) and at Day 42 (r = 0.84; P = 0.036). Peak sC5b-9 level correlated strongly with WMSI at Day 42 (r = 0.98; P = 0.005). Circulating endothelial cell activation markers sICAM-1 and sVCAM-1 were higher in the shock group during the acute phase (P < 0.01), and their peak levels correlated with sC5b-9 peak level in the whole HF population (r = 0.32; P = 0.014 and r = 0.30; P = 0.022, respectively).

    CONCLUSIONS: Complement activation discriminated cardiogenic shock from non-shock in acute ST-elevation myocardial infarction complicated by HF and correlated with regional contractility and endothelial cell activation, suggesting a pathogenic role of complement in this condition.

  • 36.
    Orrem, Hilde L
    et al.
    Oslo University Hospital, Rikshospitalet, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Rikshospitalet, Norway.
    Pischke, Søren E
    Oslo University Hospital, Rikshospitalet, Norway.
    Kleveland, Ola
    St. Olavs Hospital, Trondheim, Norway.
    Ekholt, Karin
    Oslo University Hospital, Rikshospitalet, Norway.
    Aukrust, Pål
    Oslo University Hospital, Norway.
    Halvorsen, Bente
    Oslo University Hospital, Norway.
    Gullestad, Lars
    University of Oslo, Norway.
    Barratt-Due, Andreas
    Oslo University Hospital, Rikshospitalet, Norway.
    Mollnes, Tom E
    Oslo University Hospital, Rikshospitalet, Norway.
    The IL-6 receptor inhibitor tocilizumab attenuated expression of C5a receptor 1 and 2 in patients with myocardial infarction2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 128-128Article in journal (Refereed)
  • 37.
    Orrem, Hilde L.
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Shetelig, Christian
    Univ Oslo, Norway;Oslo Univ Hosp Ulleval, Norway.
    Ueland, Thor
    Univ Oslo, Norway.;Oslo Univ Hosp, Norway;Univ Tromso, Norway.
    Limalanathan, Shanmuganathan
    Oslo Univ Hosp Ulleval, Norway;Feiring Heart Clin, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Husebye, Trygve
    Oslo Univ Hosp Ulleval, Norway;Univ Oslo, Norway.
    Aukrust, Pal
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Seljeflot, Ingebjorg
    Univ Oslo, Norway;Oslo Univ Hosp Ulleval, Norway.
    Hoffmann, Pavel
    Univ Oslo, Norway;Oslo Univ Hosp Ulleval, Norway.
    Eritsland, Jan
    Oslo Univ Hosp Ulleval, Norway.
    Mollnes, Tom E.
    Oslo Univ Hosp, Norway;Univ Tromso, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Norwegian Univ Sci, Norway.
    Andersen, Geir Oystein
    Oslo Univ Hosp Ulleval, Norway;Univ Oslo, Norway.
    Yndestad, Arne
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction2018In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 268, p. 187-192Article in journal (Refereed)
    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.

  • 38.
    Otterdal, K.
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Portillo, A.
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Astrup, E.
    Oslo University Hospital Rikshospitalet, Norway.
    Ludviksen, J. K.
    Nordland Hospital, Norway.
    Schjalm, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Raoult, D.
    Université de la Mediterranée, France.
    Olano, J. P.
    University of Texas Medical Branch, USA.
    Halvorsen, B.
    Oslo University Hospital Rikshospitalet, Norway.
    Oteo, J. A.
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Aukrust, P.
    Oslo University Hospital Rikshospitalet, Norway.
    Mollnes, T. E.
    Nordland Hospital, Norway ; Oslo University Hospital Rikshospitalet, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    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 vivo2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1204-1205, article id 161Article in journal (Refereed)
  • 39.
    Otterdal, K
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Portillo, A
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Astrup, E
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Ludviksen, J K
    Nordland Hospital, Norway.
    Schjalm, C
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Raoult, D
    Université de la Mediterranée, France.
    Olano, J P
    University of Texas Medical Branch, USA.
    Halvorsen, B
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Oteo, J A
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Aukrust, P
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Mollnes, T E
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway ; Nordland Hospital, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    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.2016In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 22, no 8, p. 734.e1-734.e6Article in journal (Refereed)
    Abstract [en]

    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.

  • 40.
    Otterdal, Kari
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Portillo, Aránzazu
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Astrup, Elisabeth
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Ludviksen, Judith
    Research Laboratory Nordland Hospital, Norway.
    Davì, Giovanni
    University of Chieti, Italy.
    Holm, Sverre
    Oslo University Hospital Rikshospitalet, Norway ; Hospital for Rheumatic Diseases, Norway.
    Santilli, Francesca
    University of Chieti, Italy.
    Vitale, Giustina
    University of Palermo, Italy.
    Raoult, Didier
    Université de la Mediterranée, France.
    Olano, Juan P
    University of Texas Medical Branch, USA.
    Schjalm, Camilla
    University of Oslo, Norway ; Oslo University Hospital Rikshospitalet, Norway.
    Halvorsen, Bente
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Oteo, José A
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Mollnes, Tom Eirik
    University of Oslo, Norway ; Research Laboratory Nordland Hospital, Norway ; Oslo University Hospital Rikshospitalet, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Aukrust, Pål
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    High serum CXCL10 in Rickettsia conorii infection is endothelial cell mediated subsequent to whole blood activation.2016In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 83, p. 269-274Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The pathophysiological hallmark of Rickettsia conorii (R. conorii) infection comprises infection of endothelial cells with perivascular infiltration of T-cells and macrophages. Although interferon (IFN)-γ-induced protein 10 (IP-10)/CXCL10 is induced during vascular inflammation, data on CXCL10 in R. conorii infection is scarce.

    METHODS: Serum CXCL10 was analyzed in two cohorts of southern European patients with R. conorii infection using multiplex cytokine assays. The mechanism of R. conorii-induced CXCL10 release was examined ex vivo using human whole blood interacting with endothelial cells.

    RESULTS: (i) At admission, R. conorii infected patients had excessively increased CXCL10 levels, similar in the Italian (n=32, ∼56-fold increase vs controls) and the Spanish cohort (n=38, ∼68-fold increase vs controls), followed by a marked decrease after recovery. The massive CXCL10 increase was selective since it was not accompanied with similar changes in other cytokines. (ii) Heat-inactivated R. conorii induced a marked CXCL10 increase when whole blood and endothelial cells were co-cultured. Even plasma obtained from R. conorii-exposed whole blood induced a marked CXCL10 release from endothelial cells, comparable to the levels found in serum of R. conorii-infected patients. Bacteria alone did not induce CXCL10 production in endothelial cells, macrophages or smooth muscle cells.

    CONCLUSIONS: We show a massive and selective serum CXCL10 response in R. conorii-infected patients, likely reflecting release from infected endothelial cells characterized by infiltrating T cells and monocytes. The CXCL10 response could contribute to T-cell infiltration within the infected organ, but the pathologic consequences of CXCL10 in clinical R. conorii infection remain to be defined.

  • 41.
    Shahini, Negar
    et al.
    Oslo University Hospital, Rikshospitalet, Norway.
    Michelsen, Annika E
    University of Oslo, Norway.
    Nilsson, Per H.
    University of Oslo, Norway.
    Ekholt, Karin
    University of Oslo, Norway.
    Gullestad, Lars
    Oslo University Hospital, Rikshospitalet, Norway.
    Broch, Kaspar
    Oslo University Hospital, Rikshospitalet, Norway.
    Dahl, Christen P
    Oslo University Hospital, Rikshospitalet, Norway.
    Aukrust, Pål
    Oslo University Hospital, Rikshospitalet, Norway.
    Ueland, Thor
    Oslo University Hospital, Rikshospitalet, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital, Rikshospitalet, Norway.
    Yndestad, Arne
    Oslo University Hospital, Rikshospitalet, Norway.
    Louwe, Mieke C
    Oslo University Hospital, Rikshospitalet, Norway.
    The alternative complement pathway is dysregulated in patients with chronic heart failure2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 127-127Article in journal (Refereed)
  • 42.
    Shahini, Negar
    et al.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Michelsen, Annika E
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Norway;Oslo University Hospital, Norway.
    Ekholt, Karin
    University of Oslo, Norway.
    Gullestad, Lars
    University of Oslo, Norway;Oslo University Hospital, Norway.
    Broch, Kaspar
    Oslo University Hospital, Norway.
    Dahl, Christen P.
    Oslo University Hospital, Norway.
    Aukrust, Pål
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Ueland, Thor
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Mollnes, Tom Eirik
    University of Oslo, Norway;Oslo University Hospital, Norway;University of Tromsø, Norway;Norwegian University of Science and Technology, Norway.
    Yndestad, Arne
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Louwe, Mieke C.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    The alternative complement pathway is dysregulated in patients with chronic heart failure2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-10, article id 42532Article in journal (Refereed)
    Abstract [en]

    The complement system, an important arm of the innate immune system, is activated in heart failure (HF). We hypothesized that HF patients are characterized by an imbalance of alternative amplification loop components; including properdin and complement factor D and the alternative pathway inhibitor factor H. These components and the activation product, terminal complement complex (TCC), were measured in plasma from 188 HF patients and 67 age- and sex- matched healthy controls by enzyme immunoassay. Our main findings were: (i) Compared to controls, patients with HF had significantly increased levels of factor D and TCC, and decreased levels of properdin, particularly patients with advanced clinical disorder (i.e., NYHA functional class IV), (ii) Levels of factor D and properdin in HF patients were correlated with measures of systemic inflammation (i.e., C-reactive protein), neurohormonal deterioration (i.e., Nt-proBNP), cardiac function, and deteriorated diastolic function, (iii) Low levels of factor H and properdin were associated with adverse outcome in univariate analysis and for factor H, this was also seen in an adjusted model. Our results indicate that dysregulation of circulating components of the alternative pathway explain the increased degree of complement activation and is related to disease severity in HF patients.

  • 43. Teramura, Yuji
    et al.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Magnusson, Peetra U.
    Qu, Hongchang
    Ricklin, Daniel
    Hong, Jaan
    Lambris, John D.
    Nilsson, Bo
    Autoregulation of thromboinflammation on biomaterials and cells by a novel therapeutic coating technique2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1140-1140Article in journal (Other academic)
  • 44.
    Thomas, Anub Mathew
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    McAdam, Martin B.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Complement (C5)-inhibition attenuates heme-induced inflammation in human whole blood2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 220-220Article in journal (Other academic)
  • 45.
    Thomas, Anub Mathew
    et al.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Lindenskov, Paal H H
    Oslo University Hospital, Norway.
    Rørtveit, Runa
    Norwegian University of Life Sciences Oslo/Ås, Norway.
    Solberg, Rønnaug
    Oslo University Hospital, Norway.
    Saugstad, Ola Didrik
    Oslo University Hospital, Norway.
    Berglund, Magnus M
    Swedish Orphan Biovitrum.
    Strömberg, Patrik
    Swedish Orphan Biovitrum.
    Jansen, Johan Høgset
    Norwegian University of Life Sciences Oslo/Ås, Norway.
    Castellheim, Albert
    Queen Silvia Children's Hospital.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway;Nordland Hospital, Norway;University of Tromsø, Norway.
    Barratt-Due, Andreas
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Combined inhibition of C5 and CD14 attenuates systemic inflammation in a newborn pig-model of meconium aspiration syndrome2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 166-167Article in journal (Refereed)
  • 46.
    Thomas, Anub Mathew
    et al.
    Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway.
    Lindenskov, Paal H H
    Oslo University Hospital, Norway.
    Rørtveit, Runa
    Norwegian University of Life Sciences, Norway.
    Solberg, Rønnaug
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Saugstad, Ola Didrik
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Berglund, Magnus M
    Swedish Orphan Biovitrum, Stockholm.
    Strömberg, Patrik
    Swedish Orphan Biovitrum, Stockholm.
    Lau, Corinna
    Nordland Hospital, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway.
    Jansen, Johan Høgset
    Norwegian University of Life Sciences, Norway.
    Castellheim, Albert
    Sahlgrenska Academy, University of Gothenburg.
    Mollnes, Tom Eirik
    Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway;Nordland Hospital, Norway;Norwegian University of Science and Technology, Norway;University of Tromsø, Norway.
    Barratt-Due, Andreas
    Oslo University Hospital, Rikshospitalet, Norway;University of Oslo, Norway.
    Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.2018In: Neonatology, ISSN 1661-7800, E-ISSN 1661-7819, Vol. 113, no 4, p. 322-330Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors.

    OBJECTIVES: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model.

    METHODS: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA.

    RESULTS: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14.

    CONCLUSION: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

  • 47.
    Wibroe, Peter Popp
    et al.
    Univ Copenhagen, Denmark.
    Anselmo, Aaron C
    Univ Calif Santa Barbara, USA.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Norway ;Oslo Univ Hosp, Rikshosp, NorwayRikshospitalet.
    Sarode, Apoorva
    Univ Calif Santa Barbara, USA.
    Gupta, Vivek
    St Johns Univ, USA.
    Urbanics, Rudolf
    Semmelweis Univ, Hungary.
    Szebeni, Janos
    Semmelweis Univ, Hungary.
    Hunter, Alan Christy
    Montfort Univ, UK.
    Mitragotri, Samir
    Univ Calif Santa Barbara, USA.
    Mollnes, Tom Eirik
    University of Oslo, Norway ;Oslo Univ Hosp, Rikshosp, NorwayRikshospitalet ; Nordland Hosp, Norway ; Univ Tromso, Norway ; Norwegian Univ Sci & Technol, Norway.
    Moghimi, Seyed Moein
    Univ Copenhagen, Denmark ; Univ Durham, UK.
    Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.2017In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 12, no 6, p. 589-594Article in journal (Refereed)
    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.

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