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Daniela Droppa-Almeida, Elton Franceschi, Francine Ferreira Padilha
Caseous lymphadenitis (CLA) is a disease caused by Corynebacterium pseudotuberculosis bacteria that affects sheep and goats. The absence of a serologic diagnose is a factor that contributes for the disease dissemination, and due to the formation of granuloma, the treatment is very expensive. Therefore, prophylaxis is the approach with best cost-benefit relation; however, it still lacks an effective vaccine. In this sense, this work seeks to apply bioinformatic tools to design an effective vaccine against CLA, using CP40 protein as standard for the design of immunodominant epitopes, from which a total of 6 sequences were obtained, varying from 10 to 16 amino acid residues...
2018: Bioinformatics and Biology Insights
Martijn van Griensven, Daniel Ricklin, Stephanie Denk, Rebecca Halbgebauer, Christian K Braun, Anke Schultze, Felix Hönes, Sofia Koutsogiannaki, Alexandra Primikyri, Edimara Reis, David Messerer, Sebastian Hafner, Peter Radermacher, Ali-Reza Biglarnia, Ranillo R G Resuello, Joel V Tuplano, Benjamin Mayer, Kristina Nilsson, Bo Nilsson, John D Lambris, Markus Huber-Lang
Trauma-induced hemorrhagic shock (HS) plays a decisive role in the development of immune, coagulation, and organ dysfunction often resulting in a poor clinical outcome. Imbalanced complement activation is intricately associated with the molecular danger response and organ damage after HS. Thus, inhibition of the central complement component C3 as turnstile of both inflammation and coagulation is hypothesized as a rational strategy to improve the clinical course after HS.Applying intensive care conditions, anaesthetized, monitored, and protectively ventilated non-human primates (NHP; cynomolgus monkeys) received a pressure-controlled severe HS (60 min at MAP 30 mmHg) with subsequent volume resuscitation...
February 14, 2018: Shock
Tetsuhiro Kajikawa, Ruel A Briones, Ranillo R G Resuello, Joel V Tuplano, Edimara S Reis, Evlambia Hajishengallis, Cristina A G Garcia, Despina Yancopoulou, John D Lambris, George Hajishengallis
Periodontitis is a chronic inflammatory disease associated with overactivation of the complement system. Recent preclinical studies suggest that host-modulation therapies may contribute to effective treatment of human periodontitis, which may lead to loss of teeth and function if untreated. We previously showed that locally administered AMY-101 (Cp40), a peptidic inhibitor of the central complement component C3, can inhibit naturally occurring periodontitis in non-human primates (NHPs) when given once a week...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
Evangelia Vlachodimitropoulou, Yu-Lin Chen, Maciej Garbowski, Pimpisid Koonyosying, Bethan Psaila, Martha Sola-Visner, Nichola Cooper, Robert Hider, John Porter
Eltrombopag (ELT) is a thrombopoietin receptor agonist reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β2 =35). Clinically achievable concentrations (1 µM) progressively mobilized cellular iron from hepatocyte, cardiomyocyte, and pancreatic cell lines, rapidly decreasing intracellular reactive oxygen species (ROS) and also restoring insulin secretion in pancreatic cells...
October 26, 2017: Blood
Susann Wolf-Grosse, Anne Mari Rokstad, Syed Ali, John D Lambris, Tom E Mollnes, Asbjørn M Nilsen, Jørgen Stenvik
Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs...
2017: International Journal of Nanomedicine
Wanderson M Silva, Fernanda A Dorella, Siomar C Soares, Gustavo H M F Souza, Thiago L P Castro, Núbia Seyffert, Henrique Figueiredo, Anderson Miyoshi, Yves Le Loir, Artur Silva, Vasco Azevedo
BACKGROUND: Corynebacterium pseudotuberculosis biovar ovis, a facultative intracellular pathogen, is the etiologic agent of caseous lymphadenitis in small ruminants. During the infection process, C. pseudotuberculosis changes its gene expression to resist different types of stresses and to evade the immune system of the host. However, factors contributing to the infectious process of this pathogen are still poorly documented. To better understand the C. pseudotuberculosis infection process and to identify potential factors which could be involved in its virulence, experimental infection was carried out in a murine model using the strain 1002_ovis and followed by a comparative proteomic analysis of the strain before and after passage...
March 22, 2017: BMC Microbiology
Morten Harboe, Christina Johnson, Stig Nymo, Karin Ekholt, Camilla Schjalm, Julie K Lindstad, Anne Pharo, Bernt Christian Hellerud, Kristina Nilsson Ekdahl, Tom Eirik Mollnes, Per H Nilsson
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...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Alexandra Primikyri, Malvina Papanastasiou, Yiannis Sarigiannis, Sophia Koutsogiannaki, Edimara S Reis, Joel V Tuplano, Ranillo R G Resuello, Bo Nilsson, Daniel Ricklin, John D Lambris
Cp40 is a 14-amino acid cyclic analog of the peptidic complement inhibitor compstatin that binds with sub-nanomolar affinity to complement component C3 and has already shown promise in various models of complement-related diseases. The preclinical and clinical development of this compound requires a robust, accurate, and sensitive method for quantitatively monitoring Cp40 in biological samples. In this study, we describe the development and validation of an ultra-high performance liquid chromatography electrospray mass spectrometry method for the quantitation of Cp40 in human and non-human primate (NHP) plasma...
January 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Azadeh Shadnezhad, Andreas Naegeli, Mattias Collin
BACKGROUND: C. pseudotuberculosis is an important animal pathogen that causes substantial economical loss in sheep and goat farming. Zoonotic infections in humans are rare, but when they occur they are often severe and difficult to treat. One of the most studied proteins from this bacterium, the secreted protein CP40 is being developed as a promising vaccine candidate and has been characterized as a serine protease. In this study we have investigated if CP40 is an endoglycosidase rather than a protease...
November 8, 2016: BMC Microbiology
Joyce Pham, Andreas Kreyssig, Alan I Goldman, Gordon J Miller
A new icosahedral quasicrystalline phase, CaAu4.5-x Al1.5+x [0.11 ≤ x ≤ 0.40(6); CaAu4.4 Al1.6 , aQC = 5.383(4) Å, and Pm3̅ 5̅], and its lowest-order 1/0 cubic crystalline approximant phase, CaAu3+x Al1-x [0 ≤ x ≤ 0.31(1); a = 9.0766(5)-9.1261(8) Å, Pa3̅ (No. 205), and Pearson symbol cP40], have been discovered in the Ca-poor region of the Ca-Au-Al system. In the crystalline approximant, eight [Au3-x Al1+x ] tetrahedra fill the unit cell, and each tetrahedron is surrounded by four Ca atoms, thus forming a three-dimensional network of {Ca4/4 [Au3-x Al1+x ]} tetrahedral stars...
October 17, 2016: Inorganic Chemistry
Jan-Michael Abicht, Ioannis Kourtzelis, Bruno Reichart, Sophia Koutsogiannaki, Alexandra Primikyri, John D Lambris, Triantafyllos Chavakis, Lesca Holdt, Alexander Kind, Sonja Guethoff, Tanja Mayr
BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3. METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function...
January 2017: Xenotransplantation
Margaret A Lindorfer, Erika M Cook, Edimara S Reis, Daniel Ricklin, Antonio M Risitano, John D Lambris, Ronald P Taylor
During malarial anemia, 20 uninfected red blood cells (RBCs) are destroyed for every RBC infected by Plasmodium falciparum (Pf). Increasing evidence indicates an important role for complement in destruction of uninfected RBCs. Products of RBC lysis induced by Pf, including the digestive vacuole and hematin, activate complement and promote C3 fragment deposition on uninfected RBCs. C3-opsonized cells are then subject to extravascular destruction mediated by fixed tissue macrophages which express receptors for C3 fragments...
October 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
George Hajishengallis, Evlambia Hajishengallis, Tetsuhiro Kajikawa, Baomei Wang, Despina Yancopoulou, Daniel Ricklin, John D Lambris
Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss...
June 2016: Seminars in Immunology
Alice Gustavsen, Stig Nymo, Anne Landsem, Dorte Christiansen, Liv Ryan, Harald Husebye, Corinna Lau, Søren E Pischke, John D Lambris, Terje Espevik, Tom E Mollnes
BACKGROUND: Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood. METHODS: Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry...
July 1, 2016: Journal of Infectious Diseases
Daniela Droppa-Almeida, Wanessa L P Vivas, Katharina Kelly O Silva, Andrea F S Rezende, Simone Simionatto, Roberto Meyer, Isabel B Lima-Verde, Odir Delagostin, Sibele Borsuk, Francine F Padilha
BACKGROUND: Caseous Lymphadenitis (CLA) is a contagious, infectious, chronic disease caused by Corynebacterium pseudotuberculosis, which affects mainly sheep and goats. The clinical prevalence of CLA in Brazil is 30%, resulting in decreased milk production, weight loss, and unusable meat and leather. Prophylaxis is based on vaccination; however, current vaccinations do not offer effective protection against the infection, which makes the development of a new vaccine essential to control this disease...
February 17, 2016: Vaccine
Tomoki Maekawa, Ruel A Briones, Ranillo R G Resuello, Joel V Tuplano, Evlambia Hajishengallis, Tetsuhiro Kajikawa, Sophia Koutsogiannaki, Cristina A G Garcia, Daniel Ricklin, John D Lambris, George Hajishengallis
AIM: Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally occurring periodontitis in non-human primates (NHPs). MATERIALS AND METHODS: Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for 6 weeks followed by a 6-week follow-up period...
March 2016: Journal of Clinical Periodontology
Junxiang Wang, Lu Wang, Ying Xiang, Daniel Ricklin, John D Lambris, Gang Chen
Simple and reliable methods for evaluating the inhibitory effects of drug candidates on complement activation are essential for preclinical development. Here, using an immortalized porcine aortic endothelial cell line (iPEC) as target, we evaluated the feasibility and effectiveness of an in vitro xenoantibody-mediated complement-dependent cytotoxicity (CDC) model for evaluating the complement inhibitory activity of Cp40, a potent analog of the peptidic C3 inhibitor compstatin. The binding of human xenoantibodies to iPECs led to serum dilution-dependent cell death...
January 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Yuzhou Zhang, Dingwu Shao, Daniel Ricklin, Brieanna M Hilkin, Carla M Nester, John D Lambris, Richard J H Smith
C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases caused by uncontrolled activation of the alternative complement pathway. Nearly half of patients progress to end stage renal failure within 10 years. Cp40, a second-generation compstatin analog in clinical development, is a 14 amino-acid cyclic peptide that selectively inhibits complement activation in humans and non-human primates by binding to C3 and C3b. We hypothesized that by targeting C3 Cp40 would provide an effective treatment for C3G...
August 2015: Immunobiology
Laura Evgin, Sergio A Acuna, Christiano Tanese de Souza, Monique Marguerie, Chantal G Lemay, Carolina S Ilkow, C Scott Findlay, Theresa Falls, Kelley A Parato, David Hanwell, Alyssa Goldstein, Roberto Lopez, Sandra Lafrance, Caroline J Breitbach, David Kirn, Harold Atkins, Rebecca C Auer, Joshua M Thurman, Gregory L Stahl, John D Lambris, John C Bell, J Andrea McCart
Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement...
June 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Judson W Silva, Daniela Droppa-Almeida, Sibele Borsuk, Vasco Azevedo, Ricardo W Portela, Anderson Miyoshi, Flávia S Rocha, Fernanda A Dorella, Wanessa L Vivas, Francine F Padilha, Maria L Hernández-Macedo, Isabel B Lima-Verde
BACKGROUND: Caseous lymphadenitis (CLA) is an infectious disease that affects small ruminants and is caused by Corynebacterium pseudotuberculosis. This disease is responsible for high economic losses due to condemnation and trim of infected carcasses, decreased leather and wool yield, loss of sales of breeding stock and deaths from internal involvement. Treatment is costly and ineffective; the most cost-effective strategy is timely immunisation. Various vaccine strategies have been tested, and recombinant vaccines are a promising alternative...
2014: BMC Veterinary Research
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