The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and... Show moreThe Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies. Show less
In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we... Show moreIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, alpha-actinin-4 and talin-1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin-1 is a specific proteolytic target of calpain-1, we investigated a potential trigger of calpain activation and talin-1 degradation using human ex vivo precision-cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain-1 by transforming growth factor-beta generated proteolytic fragments of talin-1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain-1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies. Show less
Despite decennia of research and numerous successful interventions in the preclinical setting, renal ischemia reperfusion (IR) injury remains a major problem in clinical practice, pointing toward a... Show moreDespite decennia of research and numerous successful interventions in the preclinical setting, renal ischemia reperfusion (IR) injury remains a major problem in clinical practice, pointing toward a translational gap. Recently, two clinical studies on renal IR injury (manifested either as acute kidney injury or as delayed graft function) identified metabolic derailment as a key driver of renal IR injury. It was reasoned that these unambiguous metabolic findings enable direct alignment of clinical with preclinical data, thereby providing the opportunity to elaborate potential translational hurdles between preclinical research and the clinical context. A systematic review of studies that reported metabolic data in the context of renal IR was performed according to the PRISMA guidelines. The search (December 2020) identified 35 heterogeneous preclinical studies. The applied methodologies were compared, and metabolic outcomes were semi-quantified and aligned with the clinical data. This review identifies profound methodological challenges, such as the definition of IR injury, the follow-up time, and sampling techniques, as well as shortcomings in the reported metabolic information. In light of these findings, recommendations are provided in order to improve the translatability of preclinical models of renal IR injury. Show less
Doppenberg, J.B.; Nijhoff, M.F.; Engelse, M.A.; Koning, E.J.P. de 2021
Due to a shortage of donation after brain death (DBD) organs, donation after circulatory death (DCD) is increasingly performed. In the field of islet transplantation, there is uncertainty regarding... Show moreDue to a shortage of donation after brain death (DBD) organs, donation after circulatory death (DCD) is increasingly performed. In the field of islet transplantation, there is uncertainty regarding the suitability of DCD pancreas in terms of islet yield and function after islet isolation. The aim of this study was to investigate the potential use of DCD pancreas for islet transplantation. Islet isolation procedures from 126 category 3 DCD and 258 DBD pancreas were performed in a 9-year period. Islet yield after isolation was significantly lower for DCD compared to DBD pancreas (395 515 islet equivalents [IEQ] and 480 017 IEQ, respectively; p = .003). The decrease in IEQ during 2 days of culture was not different between the two groups. Warm ischemia time was not related to DCD islet yield. In vitro insulin secretion after a glucose challenge was similar between DCD and DBD islets. After islet transplantation, DCD islet graft recipients had similar graft function (AUC C-peptide) during mixed meal tolerance tests and Igls score compared to DBD graft recipients. In conclusion, DCD islets can be considered for clinical islet transplantation. Show less
This report is the second output from the Joint Research Centre’s (JRC) Enlightenment 2.0 multi-annual research programme. The work started with the classical Enlightenment premise that reason is... Show moreThis report is the second output from the Joint Research Centre’s (JRC) Enlightenment 2.0 multi-annual research programme. The work started with the classical Enlightenment premise that reason is the primary source of political authority and legitimacy. Recognising that advances in behavioural, decision and social sciences demonstrate that we are not purely rational beings, we sought to understand the other drivers that influence political decision-making. The first output “Understanding our political nature: how to put knowledge and reason at the heart of policymaking” published in 20191, addressed some of the most pressing political issues of our age. However, some areas that we consider crucial to providing an updated scientific model of the drivers of political decision-making were not fully addressed. One of them is the impact of our contemporary digital information space on the socio-psychological mechanisms of opinion formation, decision-making and political behaviour. The JRC, together with a team of renowned experts addresses this knowledge deficit in a report that synthesises the knowledge about digital technology, democracy and human behaviour to enable policymakers to safeguard a participatory and democratic European future through legislation that aligns with human thinking and behaviour in a digital context. It is hoped that this report will prove useful as policymakers reflect upon the forthcoming European Democracy Action Plan, the Digital Services Act, the EU Citizenship Report 2020, as well as on how to legislate against disinformation. The report has been written in spring/summer of 2020 when the COVID-19 pandemic took hold of Europe and the world. During this time, our democracies suffered while technology played a crucial role in keeping societies functioning in times of lockdown. From remote distance education to teleworking, religious services to staying in touch with family and friends, for many but not all, everyday activities moved online. Additionally, technological applications and initiatives multiplied in an attempt to limit the spread of the disease, treat patients and facilitate the tasks of overworked essential personnel. Conversely, however, significant fundamental rights questions have been raised as unprecedented initiatives to track, trace and contain the pandemic using digital technologies have proven controversial. Governments invoking emergency measures in support of public health decision-making, used advanced analytics to collect, process and share data for effective front-line responses that lacked transparency and public consultation. When used as an information source, social media have been found to present a health risk that is partly due to their role as disseminators of health-related conspiracies, with non-English language speakers being at greater risk of exposure to misinformation during the crisis. It is likely that these technologies will have a long-lasting impact beyond COVID-19. Yet despite the immediacy of the crisis, the authors invite the reader to take a longer perspective on technology and democracy to get a deeper understanding of the interrelated nuances. In dark times, we seek to bring light to the importance of understanding the influence of online technologies on political behaviour and decision-making. Show less
In brain-dead donors immunological activation occurs, which deteriorates donor lung quality. Whether the complement system is activated and which pathways are herein involved, remain unknown. We... Show moreIn brain-dead donors immunological activation occurs, which deteriorates donor lung quality. Whether the complement system is activated and which pathways are herein involved, remain unknown. We aimed to investigate whether brain death (BD)-induced lung injury is complement dependent and dissected the contribution of the complement activation pathways. BD was induced and sustained for 3 hours in wild-type (WT) and complement deficient mice. C3(-/-)mice represented total complement deficiency, C4(-/-)mice represented deficiency of the classical and lectin pathway, and factor properdin (P)(-/-)mice represented alternative pathway deficiency. Systemic and local complement levels, histological lung injury, and pulmonary inflammation were assessed. Systemic and local complement levels were reduced in C3(-/-)mice. In addition, histological lung injury and inflammation were attenuated, as corroborated by influx of neutrophils and gene expressions of interleukin (IL)-6, IL-8-like KC, TNF-alpha, E-selectin, and MCP-1. In C4(-/-)mice, complement was reduced on both systemic and local levels and histological lung injury and inflammatory status were ameliorated. In P(-/-)mice, histological lung injury was attenuated, though systemic and local complement levels, IL-6 and KC gene expressions, and neutrophil influx were not affected. We demonstrated that BD-induced lung injury is complement dependent, with a primary role for the classical/lectin activation pathway. Show less
The importance of the media, both in the acquisition of knowledge, and in the formation of opinions and representations of science subjects, has been widely acknowledged in research. However,... Show moreThe importance of the media, both in the acquisition of knowledge, and in the formation of opinions and representations of science subjects, has been widely acknowledged in research. However, there is still an insufficient number of studies which focus on how young audiences specifically access, understand and create science-related content via different platforms, thereby mobilising different literacies. The present empirical study seeks to explore some bridges in this regard. By looking at a young public interested in science, namely Astronomy and Space Sciences, we intend to ascertain what they value and how they appropriate scientific information in their social relations in order to build critical scientific literacy for decision-making and the formation of opinions about science. The main results of this study confirm that informal learning plays an important role not only in the development of identification with science by young people, but also in the search for related academic and professional pathways. Although it confirms that younger people do not seek science news, the current study suggests that they do engage in seeking science-specific information according to their interests. The absence of a reflection on how science discourses and news are produced and filtered by the media and other science communication agents underlines the relevance of promoting critical science literacy, which seems to imply a link to other literacies, media literacy included. Show less
Groeneweg, K.E.; Au, Y.W.; Duijs, J.M.G.J.; Florijn, B.W.; Kooten, C. van; Fijter, J.W. de; ... ; Bijkerk, R. 2020
Simultaneous pancreas-kidney transplantation (SPKT) replaces kidney function and restores endogenous insulin secretion in patients with diabetic nephropathy (DN). Here, we aimed to identify... Show moreSimultaneous pancreas-kidney transplantation (SPKT) replaces kidney function and restores endogenous insulin secretion in patients with diabetic nephropathy (DN). Here, we aimed to identify circulating long noncoding RNAs (lncRNAs) that are associated with DN and vascular injury in the context of SPKT. Based on a pilot study and a literature-based selection of vascular injury-related lncRNAs, we assessed 9 candidate lncRNAs in plasma samples of patients with diabetes mellitus with a kidney function >35 mL/min/1.73 m(2) (DM; n = 12), DN (n = 14), SPKT (n = 35), healthy controls (n = 15), and renal transplant recipients (KTx; n = 13). DN patients were also studied longitudinally before and 1, 6, and 12 months after SPKT. Of 9 selected lncRNAs, we found MALAT1, LIPCAR, and LNC-EPHA6 to be higher in DN compared with healthy controls. SPKT caused MALAT1, LIPCAR, and LNC-EPHA6 to normalize to levels of healthy controls, which was confirmed in the longitudinal study. In addition, we observed a strong association between MALAT1, LNC-EPHA6, and LIPCAR and vascular injury marker soluble thrombomodulin and a subset of angiogenic microRNAs (miR-27a, miR-130b, miR-152, and miR-340). We conclude that specific circulating lncRNAs associate with DN-related vascular injury and normalize after SPKT, suggesting that lncRNAs may provide a promising novel monitoring strategy for vascular integrity in the context of SPKT. Show less
Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and... Show moreDelayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4 degrees C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 - vehicle, G2 - rhC1INH+heparin, and G3 - heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor alpha and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase-associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation. Show less
Kramer, C.S.M.; Franke-van Dijk, M.E.I.; Bakker, K.H.; Uyar-Mercankaya, M.; Karahan, G.E.; Roelen, D.L.; ... ; Heidt, S. 2020
In kidney transplantation, eplet mismatches between donor and recipient have been associated with de novo donor-specific antibody development. Eplets are theoretically defined configurations of... Show moreIn kidney transplantation, eplet mismatches between donor and recipient have been associated with de novo donor-specific antibody development. Eplets are theoretically defined configurations of polymorphic amino acids and require experimental verification to establish whether they can be bound by alloantibodies. Human HLA-specific monoclonal antibodies (mAbs) have been instrumental for this purpose but are largely lacking for HLA class II. In this study, we isolated single HLA-DR-specific memory B cells from peripheral blood of immunized individuals (n = 3) using HLA class II tetramers to generate recombinant human HLA-DR antigen-reactive mAbs (n = 5). Comparison of the amino acid composition of the reactive HLA alleles in relation to the antibody reactivity patterns led to identification of 3 configurations, 70Q 73A, 31F 32Y 37Y, and 14K 25Q recognized, respectively, by HLA-DRB1*01:01, HLA-DRB1*04:01, and HLA-DRB1*07:01 antigen-reactive mAbs. The first 2 correspond to eplets 70QA and 31FYY and can now be considered antibody verified. The latter indicates that eplet 25Q needs to be redefined before being considered as antibody verified. Generation and reactivity analysis of human HLA-DR mAbs allowed for identification of amino acid configurations corresponding to known eplets, whereas the other patterns may be used to redefine eplets with similar, but not identical predicted amino acid composition. Show less
The Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27,... Show moreThe Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27, 2019, held in Pittsburgh, Pennsylvania. At the meeting, the 14th Banff Conference, presentations directly and peripherally related to the topic of "digital pathology" were presented; and discussions before, during, and after the meeting have resulted in a list of issues to address for the DPWG. Included are practice standardization, integrative approaches for study classification, scoring of histologic parameters (eg, interstitial fibrosis and tubular atrophy and inflammation), algorithm classification, and precision diagnosis (eg, molecular pathways and therapeutics). Since the meeting, a survey with international participation of mostly pathologists (81%) was conducted, showing that whole slide imaging is available at the majority of centers (71%) but that artificial intelligence (AI)/machine learning was only used in approximate to 12% of centers, with a wide variety of programs/algorithms employed. Digitalization is not just an end in itself. It also is a necessary precondition for AI and other approaches. Discussions at the meeting and the survey highlight the unmet need for a Banff DPWG and point the way toward future contributions that can be made. Show less
Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir... Show moreAbacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ individuals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-gamma production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed. Show less
Hoe kiezen we wat de school moet meegeven aan de volgende generatie, als elke groep in de samenleving daar anders over denkt? Waarom mag de één wel met steun van de overheid programma's maken voor... Show moreHoe kiezen we wat de school moet meegeven aan de volgende generatie, als elke groep in de samenleving daar anders over denkt? Waarom mag de één wel met steun van de overheid programma's maken voor omroep of theater, en de ander niet? Wat moet worden onderzocht als niet elk onderzoek kan worden betaald? In een land waar geen enkele meerderheid zomaar zijn wil kan opleggen, zijn dat lastige vragen. "In de regel vrij" laat zien hoe Nederland in de afgelopen eeuw op eigen wijze vorm gaf aan onderwijs, cultuur en wetenschap. Een bijzondere ervaring, die bij de vraagstukken van de toekomst nog van nut kan zijn. Dit toegankelijke en rijk geïllustreerde boek verschijnt bij het honderdjarig bestaan van het ministerie van Onderwijs, Cultuur en Wetenschap. Het beschrijft een eeuw in thema's, van burgerschap tot wetenschap en van media tot Mammoetwet. Daarnaast bevat het bijzondere interviews met alle oud-ministers sinds 1973. Show less
Wunderink, H.F.; Meijden, E. van der; Blij-de Brouwer, C.S. van der; Mallat, M.J.K.; Haasnoot, G.W.; Zwet, E.W. van; ... ; Feltkamp, M.C.W. 2017
