Title Affiliations Abstract "Generation of chimeric antigen receptor expressing, T cell receptor negative CD4 helper and CD8 cytotoxic cells starting from cord blood hematopoietic precursor cells that are optimized for in vivo tumor eradication." "Department of Diagnostic Sciences, Department of Clinical chemistry, microbiology and immunology" "Using our expertise in T cell development, we will generate in vitro CD4 helper and CD8 cytotoxic T cells that express, instead of a diverse repertoire of T cell receptors, a single chimeric receptor directed against a tumor antigen. These T cells will be tested in a preclinical immune deficient mouse model for their tumor lysing capacity and for alloreactivity." "Generation of tumor-specific, single receptor CD4 helper and CDS cytotoxic cells from cord blood hematopoietic stem cells transgenic for a chimeric antigen receptor (CAR) incorporating a cytoplasmic costimulator domain" "Bart Vandekerckhove" "Department of Clinical chemistry, microbiology and immunology" "  To overcome these disadvantages of CART cells, we will investigate whether we can create these cells CART starting from a standardized product because cord blood from an accredited cord blood bank. Cord Blood Banks around the world subject to strict quality and can deliver this high-quality material for use in patients. From such an umbilical cord blood, which is pre-matched with the patient for HLA or tissue antigens, we will isolate the stem cells. This will be used to CART cells. In the laboratory, we have been able to demonstrate that we can produce large quantities CART cells in this way. This method of working moreover has the advantage that it CART cells, even though they are not of the patient's self, the patient will not attack, and a Graft versus Host Reaction trigger. These cells, since they are made from stem cells, are tolerant. Moreover, these cells CART will disappear after a while due to the fact that they are foreign to the body, so the effects are limited in time. The research will investigate whether CART cells can be generated from cord blood stem cells are more effective than the blood of the patient. This pro equally be carried out in a mouse model in which human leukemic cells. be introduced together with the CART cells. It is determined whether the CART cells are able to kill the human leukemic cells in this mouse. If this research is successful, it will make it possible CART cells from one cord blood unit, selected from one of the banks around the world, and this will be made in a standard way so that there is less variability in the response to patients and therefore possible to induce 100% of the patients healing." "Downsizing the downsized: Nanobody CDR peptidomimicry" "Steven Ballet" "Faculty of Sciences and Bioengineering Sciences, Chemistry" "Compared to conventional antibodies, Nanobodies (Nbs), antigen-binding fragments derived from heavy-chain only antibodies, are smaller, show favorable in vivo pharmacokinetics, and have the ability to bind highly specifically and efficiently to antigens. Even though Nbs are being fully validated in preclinical settings with the ultimate goal to translate them to clinical trials, their translation is cumbersome from a regulatory perspective. Besides immunogenicity issues, the requirements for production implicate extremely high costs, and these limitations advocate the development of smaller non-protein alternatives. In this proposal, we aim to identify the minimal structural components needed to mimic the high efficiency binding that is characteristic of Nbs. The most important subdomains in the antigen-recognition event are the complementarity determining region (CDR) loops, and hence cyclic peptidomimetics of the CDR loops will be constructed. Importantly, a thorough structural analysis by circular dichroism,2D-NMR and molecular modeling will allow to narrow down the conformational space of the designed mimetics. Next to the synthesis of individual CDR mimetics, the preparation of CDR strings is proposed to determine the individual contribution of each loop in the binding event. Two receptors, the β2- adrenergic receptor (β2AR) and the human epidermal growth factor receptor 2 (HER2), will be used in this project to verify the peptidomimetics’ ability to bind their antigens." "Actions required to secure the large-scale deployment of the leading CDR approaches to meet EU climate targets" "Veerle Vandeginste" "Surface and Interface Engineered Materials (SIEM)" "The rising concentration of CO2 in the atmosphere, currently about 420 ppm, is already causing extensive damage globally. Thus, there´s an urgent need to deploy CO2 removal (CDR) at very large scale to help to keep the temperature rise under 2C° (1.5C° would be better). Until recently, apart from academic research into a wide portfolio of approaches, little has been done to launch the necessary exponential growth of CDR over the next few decades. The current self-regulated market relies on an unsatisfactory patchwork of third-party verification of the removals achieved at individual sites. The sector has been negatively influenced by a lack of regulation and high-quality standards. This has allowed low-quality carbon credits to enter the market, lowering credibility and prices to levels at which high-quality permanent removals cannot compete. The Member States need the EC to intervene to kick-start a transparent and properly regulated market for high-grade CDR delivery.The purpose of the C-SINK project is to deliver to the EC a complete package of worked-up proposals to support a new or amended European legal/regulatory framework to bring high quality CDRs into the market. That package will contain pre-standards (in CEN format) covering requirements and methodologies for sampling, testing and QMS (ISO9000) upon which to build monitoring, reporting and verification systems. It will also include proposals to cover (a) environmental, social-impact and governance issues, and (b) the means of building trust in the market. This will encourage entrepreneurs to demonstrate effective and safe CDR projects and to make large investments, thus allowing the market to evolve to tackle the climate crisis.The C-SINK consortium includes organizations from 11 countries with complementary skills and expertise in the different CDR technologies, the writing of CEN and ISO standards, climate law, carbon trading, and in all of the relevant environmental and social issues." "Operating Grant Masterclass CSR government: CSR development framework for governments" "Implementing CSR actions in several government sustainability is much stronger on the agenda of Flanders. Why? Companies like the principle of voluntary CSR, which remains conceptual incontournable, but practice reveals something else. We can all of us to contribute to solutions to environmental and social problems: less often get in the car, our home or commercial building better insulation, efficient energy and water use hop about, respect for people with different views, etc. For all this one must invest in new technologies and change very often own personal behavior. And sometimes the shoe pinches: our individual efforts or undertaking efforts for a voluntary contribution to solving social and environmental problems cost money and effort. Actually a majority of consumers and managers remain averse to what economics Nobel laureate R. Coase called ""social costs"". Despite the fact that each of us benefits from a healthy environment and a healthy society, remain necessary to overcome investment and behavioral barriers difficult. Research proposal: 1. Supervision of the master CSR government. 2. Literature: inventory of available scientific knowledge on CSR actions at the level of governments. 3. Field investigation: collection of concrete experiences with CSR action. 4. valorisation" "How does internal CSR communication influence employees’ CSR engagement? An investigation of underlying mechanisms and boundary conditions" "Saskia Crucke" "Department of Marketing, Innovation and Organisation" "Many organizations today have CSR policies in place. CSR refers to an organization’s discretionary initiatives that maintain and contribute to social welfare and the environment. However, organizations often fail to implement their CSR policy in practice. As employees play a central role in the implementation of an organization’s CSR policy, the lack of employees’ CSR engagement is a possible explanation. Therefore, successfully engaging employees in CSR programs is one of the key challenges responsible organizations are facing today. Recently, several studies have called for more research on understanding what enhances employees’ CSR engagement. Researchers point out CSR communication as a key antecedent to be investigated in this context. This research project aims to increase our understanding of mechanisms and boundary conditions that explain how and when CSR communication influences employee CSR engagement. First, this project sheds light on which content characteristics in CSR communication promote employees’ CSR engagement. Second, it investigates whether the source of CSR communication can also influence employees' CSR engagement. Third, this research project investigates mechanisms and boundary conditions that influence the relationship between CSR communication and employees’ CSR engagement. To do so, it employs a quantitative research design including an experimental survey study, an experimental field study, and a multi-level longitudinal study." "Immunosuppressive effects of a CD4 receptor down-modulator: in vitro study of the signal peptide-dependent ER translocation inhibitor cyclotriazadisulfonamide (CADA)" "Kurt Vermeire" "Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy (Rega Institute)" "The small molecule cyclotriazadisulfonamide (CADA) was identified as an inhibitor of human immunodeficiency virus replication. It was shown that its antiviral potency is due to signal peptide-dependent inhibition of co-translational translocation of human CD4, the primary receptor for human immunodeficiency virus entry. The CD4 receptor plays an important role in the immune system, especially during activation of T cells by stabilizing the interaction between T cells and antigen presenting cells, by contributing to intracellular signaling and by enhancing T cell sensitivity. As CADA down-modulates the CD4 receptor, we were interested whether the compound could have some immunosuppressive potential. A possible application of CADA could then be in the prevention of allograft rejection after transplantation, as there is a need for new drugs that promote immune tolerance without the side effects observed with current immunosuppressive drugs.In this Ph.D. work we show that CADA has an in vitro immunosuppressive effect by inhibiting lymphocyte proliferation in the mixed lymphocyte reaction and after activation with CD3/CD28 beads or phytohemagglutinin. No significant inhibition of T cell activation by CADA was observed when CD4+ T cells were activated by superantigens, perhaps due to obviation of the CD4 receptor in this activation model. The immunosuppressive effect of CADA involves both CD4+ and CD8+ T cells and is probably initiated by direct down-modulation of the CD4 receptor, in combination with two newly identified targets of CADA, the CD8 receptor and the co-stimulatory molecule CD28. Immunosuppression by CADA is characterized by reduced expression of the T cell receptor complex members CD3 and TCRα/β, of the co-stimulatory molecules GITR, OX40 and 4-1BB, as well as of the α-chain of the IL-2 receptor also known as CD25. Diminished expression of CD25 is probably due to reduced intracellular phosphoSTAT5 levels in the presence of CADA and is likely involved in inhibition of lymphocyte proliferation. The level of soluble CD25, a marker of excessive T cell activation, and of several cytokines including IL-2, are decreased by treatment with CADA.As the sorting receptor sortilin was identified as an additional substrate of CADA and as it is involved in the secretion of several cytokines, we were interested whether CADA-induced down-modulation of sortilin could be involved in the immunosuppressive effect of CADA. The sortilin inhibitor AF38469 has no immunosuppressive effect in the mixed lymphocyte reaction, suggesting that sortilin is not essential for proper immune function and that down-modulation of sortilin does not contribute to the immunomodulatory effect of CADA.In vitro immunosuppression by CADA is less potent compared to the clinically used antiproliferative agent mycophenolate mofetil, but CADA is characterized by almost no in vitro cytotoxic and cytostatic effects, two promising characteristics for a new immunosuppressive agent. The immunosuppressive capacity of CADA in vitro however is more potent than that of Clenoliximab, a nondepleting anti-CD4 monoclonal antibody that reached phase II clinical trial for the treatment of rheumatoid arthritis.This Ph.D. work demonstrates a profound and consistent immunosuppressive profile of CADA in different in vitro T cell activation models and suggests that this compound has interesting characteristics for further exploration as a potential new immunosuppressive drug. Although the effects of CADA on intracellular T cell signaling and regulatory T cell function have not been elucidated yet, this study provides a solid in vitro foundation for future in vivo assessment of the immunosuppressive potential of CADA." "Nanobody CDR3 peptidomimetica as breast cancer diagnostic" "Steven Ballet" "Department of Bio-engineering Sciences, Medical Imaging and Physical Sciences, Chemistry" "Molecular imaging is a non-invasive technique that allows the study of disease-related molecular and cellular events using labeled probes that specifically interact with the biological target of inter-est. A novel class of promising molecular imaging probes consists of Nanobodies (Nbs).1 However, the clinical translation of recombinant proteins, such as Nbs, can be problematic due to immune responses or the extremely high costs associated to their development for human use. Hence, our group focuses on the development of CDR3 loop peptidomimetics of promising Nbs. The human epidermal growth factor receptor type 1 (EGFR/HER1) is a receptor that is highly expressed on the cell membrane of many carcinomas. Starting from Nbs that bind to HER1 (Nb7D12/Nb7C12),2peptide analogues of their respective CDR3 domains have been synthesized. The crystal structure of Nb7D12-HER1 reveals that the CDR3 domain does not adopt a common secondary structure and that Arg30 of the CDR1 domain plays a key role in the binding process.2 To improve the affinity of linear peptide analogues, cyclic CDR3 peptidomimetics bearing a lactam/triazole bridge between residues 105 and 111 were designed. In addition, Gly101 was replaced by Arg." "Nanobody CDR3 Peptidomimetics as Breast Cancer Diagnostics" "Steven Ballet" "Faculty of Sciences and Bioengineering Sciences, Chemistry" "Molecular imaging is a non-invasive technique that allows the study of disease-related molecular and cellular events using labeled probes that specifically interact with the biological target of inter-est. A novel class of promising molecular imaging probes consists of Nanobodies (Nbs).1 However, the clinical translation of recombinant proteins, such as Nbs, can be problematic due to immune responses or the extremely high costs associated to their development for human use. Hence, our group focuses on the development of CDR3 loop peptidomimetics of promising Nbs. The human epidermal growth factor receptor type 1 (EGFR/HER1) is a receptor that is highly expressed on the cell membrane of many carcinomas. Starting from Nbs that bind to HER1 (Nb7D12/Nb7C12),2peptide analogues of their respective CDR3 domains have been synthesized. The crystal structure of Nb7D12-HER1 reveals that the CDR3 domain does not adopt a common secondary structure and that Arg30 of the CDR1 domain plays a key role in the binding process.2 To improve the affinity of linear peptide analogues, cyclic CDR3 peptidomimetics bearing a lactam/triazole bridge between residues 105 and 111 were designed. In addition, Gly101 was replaced by Arg." "Optimization of Hybrid CAR T cells to cure HIV" "Linos Vandekerckhove" "Department of Internal Medicine and Pediatrics" "Chimeric Antigen Receptor (CAR) T cell therapy for viral infectious diseases needs to target both the infected cell and the pathogen to break the replication cycle. We have recently conceptualized a technology termed Hybrid CAR, where the cell transduced to express anti-HIV chimeric receptor simultaneously secretes potent, broadly neutralizing antibodies capable of deactivating HIV and mediating Fc receptor functions. Here we propose to verify whether the secreted antibodies protect the Hybrid CAR T cell itself from being infected. Rendering classical CAR-T cells resistant to HIV is currently accomplished by shRNA or CRISPR-mediated impairment of viral coreceptor expression. However, to ensure complete protection both the CXCR4 and CCR5 silencing or knock-out are essential since the HIV virus has the ability to switch tropism. Moreover, lack of CXCR4 and/or CCR5 expression can have detrimental effects on T cell function. In our approach, locally secreted antibodies will prevent HIV from infecting the cell without the need for coreceptor manipulation. The second goal of the project is to evaluate whether different cytokine cocktails can improve the secretory function of Hybrid CAR T cells to boost antibody production for further enhancement of this technology."