RELENT is a research project funded by the European Union's Horizon 2020 Framework Programme for Research and Innovation. RELENT stands for RELapses prevENTion in chronic autoimmune disease: common mechanisms and co-morbidities. The RELENT Consortium is a multidisciplinary group of scientists and clinical investigators whose goal it is to develop individualized treatments for chronic autoimmune diseases, such as rheumatoid arthritis and vasculitis.
Note from Prof. Renate Kain, M.D., Ph.D., Project Coordinator
Severe autoimmune and inflammatory diseases currently need to be treated with long-term immunosuppressive drugs that have significant side effects. Despite this, the outcome for individual patients varies considerably. We currently have no means of distinguishing from the outset which patients will suffer from frequent relapses of their disease – and therefore need intensive early treatment – from those who will not. The RELENT project will apply an entirely novel approach to systematically define common disease mechanisms in autoimmunity, involving a fast and high throughput discovery and validation process. By combining clinical and serological data with genetic and transcriptomic signatures to unravel the molecular mechanisms that determine disease outcome, we will be able to develop customised health care for people suffering from autoimmune disorders.
RELENT aims to shed light on the course and mechanisms of diseases, such as rheumatoid arthritis and vasculitis, and to develop improved diagnostics and intervention strategies with the expected impact of delaying the onset of chronic autoimmune diseases.
The work in the project is divided into six areas:
Identification of common pathways that influence disease outcome and response to treatment and infection (work package 1)
Identification of protein signatures that predict disease outcome and anticipate infective complications (work package 2)
The ageing immune system and its relation to the development of autoimmunity and co-morbidities (work package 3)
Pathogenic role of T cells and their interactions with myeloid cells (work package 4)
The project started on November 1, 2015 with a project duration of 54 months.
Main project objectives of RELENT
RELENT´s overall mission is to
understand common mechanisms of diseases and their relevance in co-morbidities thereby transforming the clinical outcome for patients with severe autoimmune and inflammatory diseases, and to
provide the scientific underpinning by closing the knowledge gap in common mechanisms of disease. This should result in a more individualized and thus safer and more effective management for severe autoimmune and inflammatory disease.
The RELENT project will analyse data from a variety of measurements (clinical, serological, genetic, transcriptomic) and thus develop new biomarkers for these diseases. These should allow the tailoring of the most efficacious treatment to each patient with a chronic autoimmune disease.
News and Events
Over the course of the last year a number of members of the RELENT consortium have been in the news.
RELENT 3rd General Assembly and 5th Steering Committee Meeting
The third RELENT Meeting took place in Groningen in January 2018.
After the meeting in Groningen a RELENT video was published on YouTube, the RELENT website and on our social media channels:
This video gives an overview over the RELENT project, its content and vision from the perspective of the project coordinator, one of the RELENT scientists and a patient representative.
RELENT partner Prof. Richard Kitching revealed origin of autoimmune kidney disease
Professor Richard Kitching is a team leader at the MONASH University and contributes to the RELENT project as an associated member by investigating the role of ageing of the immune system on the nature and severity of anti-MPO autoimmunity in mice. Additionally, his group analyses T helper cells and memory CD8+ cells and their potential HLA-dependent contributions to autoimmunity.
Many autoimmune diseases are linked to specific HLA MHC class II genotypes, but this risk for autoimmune manifestations can be mitigated by a protective MHC class II allele on the second chromosome. In a recent Nature paper (Ooi et al. Nature 2017), he unraveled the mechanism as to how the HLA-DR1 allele counteracts the HLA-DR15-mediated risk of anti-GBM nephritis. While CD4 T-helper cells stimulate the production of autoantibodies to anti-glomerular basement membrane (GBM) proteins, regulatory CD4 T-cells presenting the same antigenic peptide via HLA-DR1 maintain tolerance to these autoantigens in the periphery. Induction of antigen-specific regulatory T-cells could be a new therapeutic strategy to restore T-cell tolerance and to terminate the continuous production of autoantibodies in patients.
Recently, Richard Kitching and Professor Michael Hickey published novel findings about a process of intravascular antigen recognition for effector helper T cells in Nature Communications. Intravascular antigens originate from circulating pathogens, and in case of autoantigens from host-derived leukocytes, for example myeloperoxidase and proteinase 3 as observed in vasculitis patients. Intravascular monocytes adhere to glomerular capillaries of the kidney and present MHC class II antigen complexes to effector CD4 T cells thereby inducing CD4 T cell dependent glomerular inflammation. Intravascular monocytes with patrolling functions also exist in the lungs and can produce the important neutrophil recruiting chemokine CXCL2. These mechanisms may explain the organ preference, namely lung and kidney, of autoantibody mediated systemic vasculitis. Their discoveries form a solid basis for further investigations, with the ultimate aim of developing more specific treatments for patients with generalized systemic autoimmune diseases.
Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes. Westhorpe CLV, Norman MU, Hall P, Snelgrove SL, Finsterbusch M, Li A, Lo C, Tan ZH, Li S, Nilsson SK, Kitching AR, Hickey MJ. Nat Commun. 2018 Feb 21;9(1):747.
Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cell Ooi, J. D. , Petersen, J. , Tan, et al. Kitching AR, Nature. 545, 7653, p. 243-247 5
The team leader, Dr. Erik Toonen, is pleased to announce, that RELENT gives Hycult Biotech the opportunity to explore new fields of research and to deepen its insight in the fields of autoimmunity and inflammation. Hycult Biotech is moving forward in expanding its products in the area of chronic inflammatory diseases in which this topic fits well. The search for novel target proteins which are associated with RA (rheumatoid arthritis), IBD (inflammatory bowel disease) and AASV (ANCA associated systemic vasculitis) will allow the company to move further into the diagnostic field. The main task of Hycult Biotech within the RELENT consortium is to facilitate translation of project findings into marketable diagnostic immunoassays for personalized medicine (WP02). Furthermore, Hycult Biotech is actively involved in dissemination, exploitation and communication activities of project findings, both as work package 5 lead and Dr. Erik Toonen as a member of the Innovation and Exploitation Advisory Panel (IEAP).
Prof. Hans-Joachim Anders appointed associate editor
A warm welcome to the new RELENT project manager Anna Yenokyan
As the new RELENT Project Manager from ARTTIC, Anna Yenokyan replaces the previous project manager Dr. Natascha Perera who just recently got her first baby and is on parental leave. Anna Yenokyan is already experienced in managing European Horizon 2020 Research & Innovation projects. After her Master’s degree in European Politics, Anna Yenokyan has worked in several public and private organizations, namely at the European Parliament, the European and International Department of the City Council of Strasbourg, the International Relations Service of Strasbourg University and an European NGO. Through these different positions, Anna Yenokyan has developed a very good understanding of European projects and cooperation. As part of the Consortium team of the RELENT Project, Anna Yenokyan supports dissemination activities and is in charge of administrative, financial and contractual project management.
Meet the team @ Helmholtz Zentrum München
At the Helmholtz Zentrum München (German Research Center for Environmental Health) scientist aim to find new strategies for developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. In order to achieve these goals, the interaction of genetics, environmental factors and lifestyle is investigated.
In the research group of Dr. Dieter Jenne we focus on the functions and target substrates of neutrophil serine proteases, their role in immune defense, cell migration and cellular activation. Apart from the three known serine proteases of primary granules, elastase, cathepsin G and proteinase 3, a fourth member, NSP4 was discovered and characterized by us in recent years, however, its function in vivo remains to be determined. These four serine proteases are synthesized as inactive precursors, called zymogens, they are stored in cytoplasmic granules at the promyelocytic stage of neutrophil development in the bone marrow where they are converted to their active forms.
Mature neutrophils are continuously released into the blood circulation and are actively recruited to peripheral tissues in response to local infections or tissue damage. Specific danger signaling stimuli trigger the release of immediately active neutrophil serine proteases. Hence these serine proteases of neutrophils have a high destructive potential in various neutrophil-driven inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, idiopathic interstitial pneumonia, respiratory distress syndrome in preterm babies, or psoriasis. Proteolytic activities in the peri- and extracellular tissue space after reperfusion of organ transplants also originate from early infiltrating and activated neutrophils and damage vital functions of the donor organ early after surgery.
The extracellular activities of serine proteases are usually restrained by endogenous inhibitors, such as alpha-1-antitrypsin, in plasma, interstitial fluids, in the inflammatory exudate and in glandular secretions. In a preclinical mouse transplantation model, Dr. Dieter Jenne and his collaborators demonstrated that storage of donor lungs in alpha-1-antitrypsin-supplemented preservation solutions protects transplants against ischemia-reperfusion injury and improves primary graft functions in transplanted mice.
The inhibitory capabilities of endogenous inhibitors, however, are limited due to their relatively low concentrations in peripheral organs and their inactivation by various proteases at sites of acute and chronic inflammation. While small molecule or peptide-based inhibitors against individual neutrophil serine proteases have been extensively explored in the past 50 years, efforts of the pharmaceutical industry so far created very little impact in the clinic except for alpha-1-antitrypsin augmentation therapy in emphysema patients with congenital alpha-1-antitrypsin deficiency. Targeting multiple proteases of neutrophils simultaneously would generate greater beneficial effects in various pathological settings, but usage of combinatorial drugs potentiates the risks of unwanted side effects by each individual compound. Hence the group of Jenne and his collaborators persue a new therapeutic strategy of lowering the entire pool of the constitutively produced serine protease pool using a single specific inhibitory compound. To this end, cathepsin C inhibitors hold great promise for the future as cathepsin C is key enzyme which converts zymogens of serine proteases into their active biologically stable storage form. As a consequence of cathepsin C inhibition, the labile zymogens are degraded and eliminated already during biosynthesis and neutrophil development and therefore cannot damage peripheral organs.
Jessica Götzfried, PhD student in the research group of Dr. Dieter Jenne, has been awarded as the Best Speaker out of more than sixty presentations at the 34th Protease Winter School in Tiers. She presented her RELENT project and her talk entitled “Storage and transplantability of donor lungs is extended by α1-antitrypsin as an additive to Perfadex” convinced an international jury of leading experts on 12th of March 2017.
A complete and updated list of publications is available on the RELENT website:
This year started with some exciting publications in high-profile peer-reviewed scientific journals that we would like to highlight:
Lymphatic exosomes promote dendritic cell migration along guidance cues. Brown M, Johnson LA, Leone DA, Majek P, Vaahtomeri K, Senfter D, Bukosza N, Schachner H, Asfour G, Langer B, Hauschild R, Parapatics K, Hong YK, Bennett KL, Kain R, Detmar M, Sixt M, Jackson DG, Kerjaschki D J. Cell. Biol. 2018;217:2205-2221
This study reported that lymphatic endothelial cells (LECs) secrete exosome-rich endothelial vesicles (EEVs) to their basolateral side and thereby guide the migration of dendritic cells. The release of these vesicles is upregulated in the presence of inflammatory cytokines. The discovery of a basolateral promigratory layer of LEC-derived exosomes surrounding lymphatic vessels is a novel concept and has a broad impact for inflammation and cancer research.
Exploiting the S4-S5 specificity of human neutrophil proteinase 3 to improve the potency of peptidyl di(chlorophenyl)-phosphonate ester inhibitors: A kinetic and molecularmodeling analysis. Guarino C, Gruba N, Grzywa R, Dyguda-Kazimierowicz E, Hamon Y, Łȩgowska M, Skoreński M, Dallet-Choisy S, Marchand-Adam S, Kellenberger C, Jenne DE, Sieńczyk M, Lesner A, Gauthier F, Korkmaz B J. Med. Chem. 2018 Mar 8;61(5):1858-1870
This study introduces a high affinity inhibitor with specificity for proteinase 3, a neutrophil serine protease involved in inflammation, immune responses and as a target antigen in systemic vasculitis patients. The inhibitor is presented as a suitable therapeutic tool for fighting inflammatory and/or infectious diseases in which proteinase 3 is involved.
Preservation with α1-antitrypsin improves primary graft function of murine lung transplants. Götzfried J, Smirnova NF, Morrone C, Korkmaz B, Yildirim AÖ, Eickelberg O, Jenne DE. J Heart Lung Transplant. 2018, in press
Therapeutic targeting of cathepsin C: from pathophysiology to treatment. Korkmaz B, Caughey GH, Chapple I, Gauthier F, Hirschfeld J, Jenne DE, Kettritz R, Lalmanach G, Lamort AS, Lauritzen C, Łȩgowska M, Lesner A, Marchand-Adam S, McKaig SJ, Moss C, Pedersen J, Roberts H, Schreiber A, Seren S, Thakker NS. Pharmacol Ther. 2018, in press
Consequences of cathepsin C inactivation on membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis. Seren S, Rashed Abouzaid M, Eulenberg-Gustavus C, Hirschfeld J, Soliman H, Jerke U, N'Guessan K, Dallet-Choisy S, Lesner A, Lauritzen C, Schacher B, Eickholz P, Nagy N, Szell M, Croix C, Viaud-Massuard MC, Al Farraj Aldosari A, Ragunatha S, Ibrahim Mostafa M, Giampieri F, Battino M, Cornillier H, Lorette G, Stephan JL, Goizet C, Pedersen J, Gauthier F, Jenne DE, Marchand-Adam S, Chapple IL, Kettritz R, Korkmaz B. J Biol Chem. 2018, in press.
Are you interested in knowing more about the diseases that are the focus of the RELENT project? On our website you can find links to excellent on-line resources with a wealth of accurate and up to date information, specifically written for patients and the general public. They describe what is known about the causes of the diseases, how they are diagnosed and treated. You will also find the answers to many frequently asked questions and many other resources to support patients and their families.
Upcoming meetings and events
The 4th RELENT General Assembly Meeting will take place in Austria in January 2019.
RELENT has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668036. The views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out.