Type 1 diabetes (T1D) is an incurable disease, often starting in childhood, with a risk of devastating complications, premature mortality, and high social burden. It is caused by the autoimmune destruction of insulin-producing beta cells, yet the standard of care is insulin replacement, acting only at the symptom level. Thus, T1D is a disease with a high unmet need for innovative therapy. Ideally, such therapy shall suppress selectively the immune cells driving T1D without impairing protective immunity. Regulatory T cells (Tregs) are the guardians of human immune tolerance, and genetic defects in Tregs are associated with T1D. Tregs additionally possess tissue regenerative capacity, making them ideal to treat T1D in cell therapy. However, such therapy, performed with polyclonally expanded patient Tregs, showed limited efficacy in T1D. These expanded Tregs are however poor in relevant autoreactive Tregs to save insulin-producing cells. In fact, the identification and manufacturing of autoreactive Tregs remain fundamental technical challenges to successfully apply these cells in the clinic. ARTiDe aims at a breakthrough in antigen-specific Treg therapy in T1D by establishing the production of human Tregs genetically engineered to express an autoreactive T cell antigen receptor (TCR) ready for clinical use. To achieve this ambitious goal, ARTiDe combines the complementary expertise of 8 partners providing novel technologies for the systematic identification of autoantigen-specific Tregs in humans, the selection of optimal TCR to produce protective Tregs, and innovative humanized T1D pre-clinical models to test their efficacy and safety, as well as Treg supporting strategies, in vivo. World-leading biotechs for adoptive T cell therapy will establish novel GMP-compatible manufacturing of highly purified TCR-engineered Tregs. ARTiDe will deliver a Treg production process and regulatory certificates that will allow launching a phase 1 clinical trial just after the project.

The microbiota has an enormous influence on human health. CD4+ T cells play a central role in controlling the interaction with the microbiota. By specifically reacting against individual microbial species, T cells enable a mutualistic co-existence with microbes. Inappropriate T cell responses against microbes are in turn associated with inflammatory diseases. Thus, the combination of T cell specificity and functionality form the key determinant for physiological versus pathological host-microbiota interactions. So far, research on T cell-microbiota interaction is almost exclusively focussed on functional T cell subsets, whereas antigen-specificity is rarely addressed. This is a significant roadblock for developing targeted therapeutic interventions for microbiota-associated diseases. The interaction with the microbiota poses two particular challenges for adaptive immunity: first, the extremely high diversity of microbial species, and thus potential T cell targets; second, microbes are persistent and thus probably encountered chronically. Currently, we do not know (1) which microbes are targets of specific T cell reactivity in humans, (2) how the (chronic) interaction with the huge number of different microbial species is regulated by T cell specificity and function, and (3) how alterations of these parameters contribute to microbiota-associated diseases. I developed a highly sensitive technology to detect and deeply characterize microbe-specific T cells directly from human samples. MicroT will identify microbial target species of human T cells and unravel the molecular mechanisms regulating chronic interaction of T cells with the highly diverse microbiota. I will define the impact of specific T cell-microbiota interactions on chronic inflammatory diseases and upon ageing. Answering these fundamental questions of microbiota-T cell interaction will identify specific immune or microbial targets as an essential basis for rational development of novel targeted therapies.

Background: Chronic inflammatory diseases (CID) are a group of non-communicable disorders of the immune system with a lifetime prevalence of over 10% in the EU. Rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD) are two archetypal CIDs with a particularly high unmet medical need and impact on European health care systems. Objectives: The PerPrev-CID consortium aims to set up new standards for decision support tool development for preventive and early therapeutic interventions in RA and IBD. Selected main aims are: (i) To define actionable predictors from longitudinal multi-level Omics and clinical data integration In RA and IBD. We will identify markers indicating progression from pre-symptomatic to manifest disease and signatures predicting early disease relapse (ii) To develop new tools for home-based and continuous assessment of patient-related data dimensions using digital health apps/wearables, including more innovative, objective parameters, such as movement patterns, physical activity, and sleep. (iii) To assess the health-promoting effects of interfering with the tryptophan pathway in a proof-of-concept nutritional study in early RA and IBD. (iv) To study ethical, legal and economic consequences of risk assessment and early low-threshold preventive interventions. Important aspects are the communication of the risk concept, economic implications of broad testing and interventions as well as patients´ perception of the concept of risk prediction. Expected impact: We will develop prototype solutions for privacy-preserving AI-based data analysis for research and clinical application and will test a first proof-of-concept low threshold intervention in RA and IBD. Our approaches will provide a clear health benefit to the citizens of the EU by improving health outcomes, empowering joint decision making and contributing to appropriate action plans to reduce the avoidable burden of the diseases.

Europe still sees a quarter of the world's cancer cases each year, making cancer the second leading cause of death and illness in the region after cardiovascular diseases. Unless we take decisive action, lives lost to cancer in the EU are set to increase by more than 24% by 2035, making it the leading cause of death in the EU. Cross-border collaboration can address this challenge by combining data from various modalities and sources, extracting meaningful insights to deepen our understanding of cancer. However, ethical, legal, and national regulations, along with data access processes, including differing interpretations of the EU GDPR create significant hurdles. Technical interoperability issues across European cancer RIs, and patients' and citizens' rights to control who uses their personal information and for what purposes further complicate data sharing. The project will provide European researchers, SMEs, and innovators with a decentralized collaborative network, “UNCAN-CONNECT,” for cancer research. It consists of both technical components, a governance, compliance, and operational framework based on the UNCAN blueprint, with the goal of operationalizing it. The objective is to facilitate access to cancer data, promote open science, and revolutionize cancer research and treatment by co-creating an open-source federation of federations platform. It will be developed using specific use cases focused on six major cancer types: Paediatric, Lymphoid malignancies, Pancreatic cancer, Ovarian, Lung, and Prostate cancers and active collaboration with a diverse range of stakeholders, including researchers, SMEs, industrial end users, and citizens. It will build on existing European RIs such as BBMRI as well as initiatives like EOSC4CANCER, CanSERV, EUCAIM, to enable seamless storage, access, sharing, and processing of data across Member States and associated countries. This approach will foster interoperability and collaboration, accelerating progress in cancer research. This action is part of the Cancer Mission clusters of projects 'Understanding' established in 2022.