| 11. |
- Gustafsson, Gabriel, et al.
(författare)
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Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes
- 2017
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Due to its neurotoxic properties, oligomeric alpha-synuclein (α-syn) has been suggested as an attractive target for passive immunization against Parkinson’s disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic α-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf α-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria.Methods: The aim of the present study was to investigate if the accumulation of α-syn in astrocytes can be affected by α-syn oligomer-selective antibodies. Co-cultures of astrocytes, neurons, and oligodendrocytes were derived from embryonic mouse cortex and exposed to α-syn oligomers or oligomers pre-incubated with oligomer-selective antibodies.Results: In the presence of antibodies, the astrocytes displayed an increased clearance of the exogenously added α-syn, and consequently, the α-syn accumulation in the culture was markedly reduced. Moreover, the addition of antibodies rescued the astrocytes from the oligomer-induced mitochondrial impairment.Conclusions: Our results demonstrate that oligomer-selective antibodies can prevent α-syn accumulation and mitochondrial dysfunction in cultured astrocytes.
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| 12. |
- Gustafsson, Gabriel
(författare)
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Alpha-Synuclein Oligomers : Cellular Mechanisms and Aspects of Antibody Treatment
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), aggregated α-synuclein deposit inside cells within the brain. Smaller soluble α-synuclein aggregates, oligomers, are present both intra- and extracellularly. The α-synuclein oligomers are known to be particularly harmful, although the underlying neurotoxic mechanisms are not fully understood. The aim of this thesis was to investigate the pathogenic roles of α-synuclein oligomers and the possibility to target such species with antibody treatment.Passive immunotherapy with α-synuclein antibodies can lead to reduced pathology and ameliorated symptoms in transgenic mice. However, it remains unknown whether the antibodies are taken up by cells or whether they act extracellularly. In Paper I, we assessed cellular internalization of various α-synuclein monoclonal antibodies. The oligomer selective mAb47 displayed the highest uptake, which was promoted by the extracellular presence of α-synuclein.Alpha-synuclein aggregates can be found in both neurons and glial cells, but the pathogenic role of glial deposits has only been sparsely investigated. In Paper II, co-cultures of neurons and glia were exposed to α-synuclein oligomers. The astrocytes in the cultures rapidly accumulated oligomers, which were only partially degraded by lysosomes. The sustained intracellular α-synuclein deposits were associated with mitochondrial stress reactions in the astrocytes. In Paper III, we sought to explore whether the astrocytic pathology induced by α-synuclein oligomers could be ameliorated by antibody treatment. Pre-incubation of oligomers with mAb47 promoted α-synuclein clearance, reduced astrocytic accumulation and rescued cells from mitochondrial stress. We could demonstrate that binding of the antibody to its antigen in the extracellular space was crucial for these effects to occur.The progressive pathology in PD is believed to be driven by cell-to-cell spreading of α-synuclein aggregates, potentially via exosomes and other extracellular vesicles (EVs). In Paper IV, we found that either fusing α-synuclein to a non-physiological protein tag or introducing the PD-causing A53T mutation directed α-synuclein towards EV secretion. Also, EV-associated α-synuclein was particularly prone to induce toxicity in recipient cells.In conclusion, this thesis sheds new light on the cellular dysfunction related to α-synuclein pathology and on how the underlying pathogenic processes may be targeted by antibody treatment.
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| 13. |
- Gustafsson, Gabriel, et al.
(författare)
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Secretion and uptake of α-synuclein via extracellular vesicles in cultured cells
- 2018
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Ingår i: Cellular and molecular neurobiology. - : Springer Science and Business Media LLC. - 0272-4340 .- 1573-6830. ; 38:8, s. 1539-1550
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Tidskriftsartikel (refereegranskat)abstract
- In Parkinson’s disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of α-syn can influence the distribution and secretion of α-syn in human neuroblastoma cells. Different α-syn variants, including α-syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted α-syn, 0.1–2% was associated with vesicles. The major part of EV α-syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For α-syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT α-syn. Moreover, such EV-associated α-syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T α-syn displayed an increased association with EVs. Taken together, our data suggest that α-syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful α-syn species and thereby contribute to the pathology in α-synucleinopathies.
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| 14. |
- Ideland, Malin, et al.
(författare)
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Edu-preneurs in the welfare state. On how commercial actors make themselves indispensable through defining problems and offering solutions
- 2018
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Ingår i: NERA abstract book. ; , s. 480-480
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Research topic/aim: According to current debates, Swedish schools are experiencing severe problems: decreasing results in international large-scale assessments, increasing segregation, and not preparing students for job markets. This discourse has enabled an apparatus of commercial actors, ‘edu-preneurs’, offering solutions. This paper explores what happens when governing and practicing of education becomes distributed on commercial actors. The aim is to shed light on how educational policy is moved, translated, and fixed in entanglements of public and private rationalities and what this means for understandings of knowledge, teaching, and learning. Theoretical framework: We understand this growing apparatus of edu-preneurs as a result of that a shift in the responsibility of Swedish schooling is taking place (Ball, 2009). ‘Statework’, in terms of educational governance, is now carried out through an assemblage of public and private actors. This shift is understood in a historical context of neoliberalism. With Ball’s (2009) words we can call it a ‘recalibration of the state’, through which the organization of public institutions has changed – but also the meanings and practices of schooling as well as possible subjectivities for teachers and students. Methodological design: Empirically, the paper illuminates what we call the public/private statework through entering three different policy fields: research-based education, digitalization, and entrepreneurship. The data consist of a nethographical mapping of edu-preneurial companies and a close-up analysis of how three companies make themselves up as normalized educational actors. The analysis employs actor-network theory to explore of how the idea of schooling is constructed on the edu-preneurs’ websites through, formulating problems and solutions and enrolling a range of actors into the governing and practices of education. Findings and conclusions: The edu-preneurs made up themselves as taken for granted as actors, first, as defining problems: the Swedish school system is in crisis and in need for help. This is done through explicitly relating to a narrative of teaching as outdated, educational research as ‘fuzzy’ and unpractical, and schools distanced from ‘reality’ and the labour market. In the companies’ solution to this problem, they become important actors through talking about structured work, practical solutions, and modern (digital) ways of teaching. They enrol ‘friends’ into the assemblage in the shapes of education superstars, partner companies, technological devices, and policy bodies. We suggest that the companies translate the idea of schooling and carry with them epistemic implications, as well as a cultivation of desirable subjectivities. Understandings of what is useful ‘research’ as well as ‘important knowledge’ are claimed and limited. Teacher subjectivity is characterized as flexible and effective and the student subjectivity as entrepreneurial. The ideas of what knowledge is, and how teaching and learning should ‘happen’, privilege ‘business-like’ methods. Relevance to Nordic educational research: The Swedish case is interesting in a wider Nordic context since it sheds light on on-going processes in the Nordic countries through which the welfare state is transformed into a market. References: Ball, S. J. (2009). Privatising education, privatising education policy, privatising educational research: network governance and the ‘competition state’, Journal of Educational Policy, 24(1), 83-99.
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| 15. |
- Jobér, Anna, et al.
(författare)
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Doing democracy. Research Perspectives on Risks and Responsibilities within a Marketised Education. PART 1
- 2019
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Description of the symposium A general aim for school systems around the world is to prepare future citizens to participate in and contribute to society. In most western countries, this is upheld and developed within notions and practices of democracy and citizenship. Consequently, there is a close relationship between education and democracy. In times of increased global movements and diversity among students, issues of democracy therefore gain further attention, becoming a high-stake concept, recently seen in for example the new OECD framework on Global competence. At the same time, marketisation and privatisation of education rapidly change the foundations of schooling (Ball, 2009; Rizvi, & Lingard, 2010). This could be understood as parts of global transformations and trends that in many cases are supported by neoliberal visions, visions that reshape educational systems (Beach, 2010; Popkewitz, 2008). This rearrangement influences all parts of schooling and creates consequences on many levels. To name a few, the rearrangement involves profitable businesses, competitive and governing structures, digitalisation, rearranging of decision-making and responsibility, and renegotiation of discourses, positions and processes (Ball, 2009; Bunar, & Ambrose, 2016; Dovemark & Erixon Arreman, 2017; Verger, Lubienski, & Steiner-Khamsi, 2016). Furthermore, new ways of acting and communicating can be seen when policy actors, private companies, NGOs, school leaders, researchers, and lobby groups collaborate in entangled networks resulting in blurring boundaries and interwoven practices (Ball, 2018; Simons, Lundahl, & Serpieri, 2013). This in turn impacts on accountability, risk-taking, responsibility and transparency. Thus, educational spaces become fundamentally transformed and issues of democracy, societal problems, citizenship, accessibility and the like need to be renegotiated in relation to a changed educational landscape. This symposium will illuminate and discuss these changes and their consequences. For example, what happens with decision-making processes, accessibility, diversity, and political actions? What logics becomes changed, manifested or inscribed? What can be marketed, and becomes possible to sell? Could one say that citizenship and democracy have become commodities, something to trade? These questions will be addressed at the symposium alongside the discussion of the role of educational research. We stress that researchers’ engagement in education are of great importance in our European context and have the possibility to affect schools, national and international policy-makers, so called edu-preneurs and all actors involved in education. The symposium consists of contributions representing a wide range of perspectives and approaches taken by researchers from Sweden, Finland, Norway, New Zealand, and Brazil. Consequently, the symposium will mirror a variety of national and educational contexts all with the dual focus on the theme of the symposium and the theme of the conference. Many of the researchers in the symposium belong to a newly formed network called Researchers on education and marketization (the REM network) founded within the Swedish research project Education Inc. The network now consists of nineteen researchers from three countries and eight universities that in different ways problematise and scrutinise marketisation and education and the urgent and necessary issues that evolves in when education becomes marketised and new logics change the conditions for schooling. The symposium has two parts. The first part starts with an introduction given by Anna Jobér, coordinator and co-founder of the REM network followed by presentation of six papers in two sessions. They are arranged in order to give a thought-proving and interesting symposium regarding the variety of research project, methodological and theoretical perspectives as well as cultural contexts. Finally, the symposium is wrapped up by a discussant, Professor Marie Brennan https://www.vu.edu.au/contact-us/marie-brennan.
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| 16. |
- Jobér, Anna, et al.
(författare)
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Good Intentions and Altruistic Objectives : Observing ‘Edu-preneurs’ at a School Fair
- 2018
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: As an answer to a discourse on a Swedish school in crisis a large edu-political apparatus has been implemented. Arguments on e.g. decreasing results, segregation, and equal opportunities has reinforced a number of actors to enter the educational field – actors here called “edu-preneurs” (Rönnberg, 2017). The actors offer a multitude of products and services and essential parts of everyday schooling thus become outsourced on external actors using education as an arena to reach the core of the society – the children. This process, nurtured by political reforms such as the possibility to profit on public funds (Jober, submitted) has “re-calibrated” the Swedish school – from a government-dominated and unified educational system to an unruly free market (Ball, 2009; Hamilton, 2011). This market and its edu-preneurs will be investigated in the project ‘Education Inc.’, funded by the Swedish Research Council (Ideland, Axelsson, Jobér & Serder, 2016). The project aims to study how private actors and logics change the conditions for what counts as good education. Three forms of commodification of education, outlined by Molnar (2006), will be studied: (1) actors selling to schools; (2) actors selling in schools; and (3) actors buying for schools. In order to create a baseline for the Education Inc. project this paper describes one the first sub studies. This sub study aims to scrutinise foremost actors selling toschool when presenting themselves and engage with the school community at a school fair. Research Questions: The overarching aims of the Education Inc. project is to study under what conditions, in what forms and with which consequences ‘edu-preneurial’ actors engage in Swedish schools. This particular sub study focus on with what objectives do edu-preneurial companies, NGOs and their employees engage in Swedish school. Objectives: The aim of this sub study is to conceptualise and analyse processes on how good intentions and altruistic objectives are used as arguments to justify actors’ place in education. An earlier pre-study (Jobér, submitted) showed that tutoring companies, actors in the educational market, used arguments regarding children with special needs to justify their presence and actions. This pre-study raised a number of questions: Will the companies, whatever good intentions, overlook profit? Are arguments regarding children with special needs used as a lever for businesses to survive and profit rather than to help? Similar has been showed elsewhere (Dovemark & Erixon Arreman, 2017), therefore we claim there is a risk that actors in the educational market will not consider all children as profitable enough. There is therefore a need to scrutinize if money spent (through public funds) will increase profits and exclusion rather than to support inclusion, and in addition, if students with low exchange value fit into a neoliberal market. Theoretical framework: We argue that processes in Sweden, which is a traditionally strong and well-trusted welfare state, have become entangled with neoliberal rationalities (see e.g. Dahlstedt, 2009) and that ways of imagine and practice schooling today are shaped by neoliberal logics (Rizvi & Lingard, 2010). The neoliberal state has opened up for a commodification of education (Steiner-Khamsi, 2016) and educational reforms become a way to make up a specific kind of subjectivity (Ong, 2007). The marketization of education is thus not only about earning money, but also about making up meanings and practices of schooling and a certain kind of ideal citizen (Olmedo, Bailey & Ball 2013). This is what Ong (2007) conceptualizes as a neoliberalism which concerns how possible and desirable subjectivities are produced. The questions are what kind of objectives the actors put forward and how this correspond with what kind of desirable subjects that are produced in this neoliberal logic. Method: The sub study presented here will take a closer look at the actors selling to school when they attend a large school fair, SETT, which will take place in Sweden in April. In a pre-study to the larger ‘Education Inc.’ project this kind of educational ‘trade fairs’ has been identified as one of the spaces where policy becomes translated and turned into business ideas (Ideland et al, 2006). Observations will take place at this fair by four researchers. The observations will be written down using an observation scheme. The observations will also include photographs of the showcases and the messages that can be found there. In addition the research team will gather advertisement such as flyers and follow ongoing twitter flows. These data will be reflected on within the research group and finally analysed employing an analytical framework developed from the work by Callon (1986, used by, e.g., Hamilton 2011). The aim with this analysis is to more carefully explore how a problem is articulated through the actors and their relationships i.e. the problematisation moment in Callons work (1986). Callon proposes that translation of actions and actors analytically can be studied as four different moments: Problematization, Interessement, Enrolment, and Mobilization. It is the first step, the problematization moment and how a problem is articulated through the actors and their relationship that is in focus here. The problematization is the moment when actors (such as those the selling to schools at the school fair) or clusters of actors articulate a problem. It often involves a focus on a particular goal or a problem to be solved where the actors locate themselves as gatekeepers and problem solvers. Within the problematisation moment, the analysis can show what problems actors enhance (for example, in schools or in society), how do they want to solve these problems, and the argument that makes them indispensable to the problem and action. With this framework we can thus scrutinise with what kind of intentions and objectives these actors engage in Swedish school. Expected Outcomes: The hypothesis is that the observations conducted at this school fair and its following analyses will give insights in with what objectives and intention edu-preneurial companies, NGOs and their employees engage in Swedish school. Building on a pre-study (Jobér, submitted) and earlier research (e.g. Dovemark & Erixon Arreman) the hypothesis is also that the actors will bring forward a number of altruistic arguments. These might regard supporting the society to decrease widening socioeconomic gaps, including children with special needs, opening possibilities to equal opportunities for all, and reaching out to students living in rural areas of Sweden. However, as shown in above earlier studies, these are complicated arguments, given for example that a number of initiatives in the educational market, such as private tutoring, is not used at all by those with low incomes (Björkman, 2014, 21 November). There are reasons to believe that the expected outcomes from this pre-study not only will show what kind of altruistic objectives the actors use to justify their presence but also bring forward initial data that in forthcoming studies can be used to identify if the actors in educational market desire profits rather than inclusion and equal opportunities for all. References: Ball, S. (2009). Privatising education, privatising education policy, privatising educational research: network governance and the ‘competition state’, Journal of Education policy, 24(1), 83-99. Callon, M. (1986). Elements of a sociology of translation: Domestication of the Scallops and the Fishermen of St Brieuc Bay. In J. Law (Ed.), Power, Action and Belief: A New Sociology of Knowledge? London: Routledge, pp 196-233. Clarke, J. (2002). A new kind of symmetry: Actor-network theories and the new literacy studies. Studies in the Education of Adults, 34(2), 107-122. Dahlstedt, M. (2009). Governing by partnerships: dilemmas in Swedish education policy at the turn of the millennium, Journal of Education Policy, 24(6), 787–801. Dovemark, M. & Erixon Arreman, I. (2017). The implications of school marketisation for students enrolled on introductory programmes in Swedish upper secondary education. Education, Citizenship and Social Justice, 12(1), 1–14. Hamilton, M. (2011). Unruly Practices: What a sociology of translations can offer to educational policy analysis. Educational Philosophy and Theory, 43(1), 55–75. Ideland, M., Axelsson, T., Jobér, A. & Serder, M. (2016) Helping hands? Exploring school’s external actor-networks. Paper accepted for ECER, Dublin, August 2016. Jobér, A. (submitted). How to become Indispensable: Tutoring Businesses in the Education Landscape. Submitted to Special Issue of Discourse titled Politics by Other Means: STS and Research in Education. Latour, B. (2005). Reassembling the social: An introduction to actor-network theory. Oxford: Oxford University Press. Molnar, A. (2006). The Commercial Transformation of Public Education, Journal of Education Policy, 21(5), 621-640. Olmedo, A., Bailey, P. L., and Ball, S. J. (2013). To Infinity and Beyond…: heterarchical governance, the Teach For All network in Europe and the making of profits and minds. European Educational Research Journal, 12(4), 492–512. Ong, A. (2007). Neoliberalism as a mobile technology. Transactions of the Institute of British Geographers, 32(1), 3-8. Rizvi, F. & Lingard, B. (2010). Globalizing education policy. London: Routledge. Rönnberg, L. (2017). From national policy-making to global edu-business: Swedish edupreneurs on the move. Journal of Education Policy, 32(2), 234–249. Steiner-Khamsi, G. (2016). Standards are good (for) business: standardised comparison and the private sector in education. Globalisation, Societies and Education 14(2).
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| 17. |
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| 18. |
- Lindsten, Therése, et al.
(författare)
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Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-2
- 2017
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 51:1, s. 104-114
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Tidskriftsartikel (refereegranskat)abstract
- Malignant tumors, including breast cancers, are frequently infiltrated with innate immune cells and tumor-associated macrophages (TAMs) represent the major inflammatory component in stroma of many tumors. In this study, we examined the immunoreactivity of the macrophage markers CD68 and CD163 as well as the hormone receptors estrogen receptor alpha (ER alpha), progesterone receptor (PR), estrogen receptor beta 1 (ER beta 1), human epidermal growth factor receptor 2 (HER-2), matrix metalloproteinase 9 (MMP-9), urokinase-type plasminogen activator receptor (uPAR) and the proliferations marker Ki67 in 17 breast cancer biopsies. The quantitative score for CD68(+) and CD163(+) strongly indicate M2 phenotype dominance in the currently investigated biopsies. We found that an increasing level of macrophages was negatively associated with ER alpha or PR, whereas a positive association was observed for Ki-67 or uPAR. No significant association could be seen between the level of macrophage and HER-2, ER beta 1 or MMP-9 expression. Effect of conditioned media (CM) generated from cultured human M1 and M2 macrophage phenotypes were investigated on the proliferation and expression of selected markers in the T47D breast cancer cell line. We found that in contrast to the in vivo situation, in particularly the CM from M1 macrophages decreased the growth and Ki67 expression in T47D, and significantly increased ER beta 1 mRNA levels. Moreover, in accordance to the in vivo situation the CM from the macrophages decreased the expression of ER alpha protein as well as ER alpha or PR mRNA. In conclusion our results show that macrophages alone have the capability to decrease the tumor cell expression of ER alpha and PR in vitro. In the tumor environment in vivo macrophages also contribute to an increase in tumor cell expression of uPAR and Ki67, suggesting that macrophages are involved in impairing the prognosis for breast cancer patients.
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| 19. |
- Lindström, Veronica, et al.
(författare)
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Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
- 2017
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 82, s. 143-156
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Tidskriftsartikel (refereegranskat)abstract
- The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes. Alpha-synuclein oligomers were found to co-localize with the glial cells and the astrocytes were found to internalize particularly large amounts of the protein. Following ingestion, the astrocytes started to degrade the oligomers via the lysosomal pathway but, due to incomplete digestion, large intracellular deposits remained. Moreover, the astrocytes displayed mitochondrial abnormalities. Taken together, our data indicate that astrocytes play an important role in the clearance of toxic α-synuclein species from the extracellular space. However, when their degrading capacity is overburdened, α-synuclein deposits can persist and result in detrimental cellular processes.
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| 20. |
- Lundbäck, Peter, et al.
(författare)
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A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice
- 2016
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 64:5, s. 1699-1710
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Tidskriftsartikel (refereegranskat)abstract
- Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP-induced acute liver injury (APAP-ALI) and justifies development of anti-inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N-acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP-ALI. The anti-HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti-HMGB1 polyclonal antibody treatment improves survival in a model of APAP-ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti-HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP-ALI. The mouse anti-HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody-Fc backbones. Effector function-deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP-ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP-induced serum elevations of alanine aminotransferase and microRNA-122 and completely abrogated markers of APAP-induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C-X-C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1-neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP-ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1-specific therapy as a means to treat APAP-ALI and other inflammatory conditions. (Hepatology 2016;64:1699-1710).
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