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RELapses prevENTion in chronic autoimmune disease: common mechanisms and co-morbidities

Periodic Reporting for period 2 - RELENT (RELapses prevENTion in chronic autoimmune disease: common mechanisms and co-morbidities)

Reporting period: 2017-05-01 to 2018-10-31

RELENT (RELapse PrevENTion in autoimmune disease: mechanisms and co-morbidities) is a multidisciplinary consortium formed to meet the objectives of PHC 3 - 2015: Understanding common mechanisms of diseases and their relevance in co-morbidities thereby transforming the clinical outcome for patients with severe autoimmune and inflammatory diseases. These include some of the most disabling chronic diseases that affect patients of all ages, however show a predilection for either elderly females, such as rheumatoid arthritis, or younger males, like inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and various forms of vasculitis that affect both sexes. Commonly, they require treatment with long-term immunosuppressive drugs or therapeutic monoclonal antibodies or biological agents but mortality and morbidity remain high both from uncontrolled disease activity and the complications of immunosuppression, emphasising the failure of current strategies for titrating the intensity of immunosuppressive therapy to the individual needs of patients. There is an unmet need for more personalized treatment approaches based on a better understanding of the pathophysiology of these diseases to overcome the severe challenge for patients and the physicians who care for them, and for the healthcare delivery systems throughout Europe that provide the resources to do so.

The overarching purpose of the RELENT program is to provide the scientific underpinning by closing the knowledge gap in common mechanisms of disease for more individualized and thus safer and more effective management for severe autoimmune and inflammatory disease in both females and males affected by them. The Consortium will apply highly innovative approaches to overcome three challenges, namely to:
• increase knowledge of pathogenetic mechanisms that can be specific targets for therapy;
• discover predictive biomarkers that are able to identify prospectively individuals who would benefit from initial intensive immunosupressive therapy to control multiply relapsing disease and distinguish them from those with less persistent disease;
• devise effective ways to monitor the underlying immunopathogenesis of these diseases, so therapy can be accurately titrated to control its activity.

Data from the clinical response to therapeutic monoclonal antibodies, the results of genome wide association studies and recent transcriptomic data have already provided a compelling evidence of pathways or mechanisms common to different severe inflammatory diseases. RELENT consortium partners have been responsible for some of the most important of these discoveries and the proposed programme builds on this experience. They will now combine systems medicine approaches with novel approaches to pathway analysis to provide a deeper knowledge of molecular and cellular events responsible for severe autoimmune and inflammatory disease in order to improve the effectiveness of therapy and minimize the risks of its toxicity and side effects of long term immunosuppression, like infections.

The program has four specific aims each corresponding to an individual Scientific Work Package designed to:
• Combine subset analysis of genome wide association studies with classical cell biology to uncover pathways that influence the outcome of chronic autoimmune and inflammatory disease and the response to treatment in women and men (WP 01).
• Identify protein signatures that predict the outcome of chronic autoimmune and inflammatory disease, using multiplexed antigen arrays, whole proteome analysis and mass spectrometry analysis (WP 02).
• Characterise T and B cell abnormalities that predispose to autoimmunity and infection by studying the ageing immune system in health and disease (WP 03).
• Analyse pathogenic effector T cells and their control by macrophages and dendritic cells and the molecules they secrete using normal and transgenic mice expressing human proteins (WP 04).
Partners have made substantial progress on the scientific work packages in identifying novel pathways in autoimmune and inflammatory disease. The work in WP1 validated iPSC from individuals with defined genetic background and established protocols for the differentiation into different cell types and their characterization. These are currently used for experiments with sets of inhibitors of chaperone mediated autophagy to dissect mechanism of autophagy. Utilising the unique resource of biological samples from patients with autoimmune disorders and healthy subjects the partners extended the investigation of molecular markers in AAV. A preliminary GWAS of age at disease onset and vasculitic organ involvement in of two cohorts of AAV patients and analysis of data is currently ongoing. The analyses of the autoantibody repertoire and correlation network analysis of the serum proteome by highly innovative and sensitive multiplex and biomarker discovery platforms performed in WP2 identified a number of novel autoantigens and proteins that were more prevalent in active disease. If validated in independent cohorts of patients these might represent novel biomarkers of disease activity that could be used to tailor treatment to individual patients with AAV. The in-depth analysis of the interaction of auto-antibodies with the antigens they recognise by highly sensitive mass-spectrometry based proteomics allows to investigate means to specifically disrupt the pathogenic interaction and may lead to novel therapeutic interventions. Autoimmunity that affects the elderly warrants the analysis of immune cell signatures in the ageing immune system and transcriptome analyses, both in healthy aged subjects and those with autoimmune disorders. The results from studies in healthy controls in WP3 showed that numerical and/or functional changes in specific T cell subsets are associated with an ageing immune system and the development of autoimmunity. Analysis of differential expression of checkpoint molecules in immune cells suggests that age-related changes in their expression and function may lead to an unstable immune system which is prone to tolerance failure. The results of WP4 have yielded an unexpected and to date unknown cross-reactivity between autoantigens that may provide a breakthrough in understanding the variety of disease phenotypes and the autoantibodies that are associated with them in AAV. The comprehensive approach of RELENT research of dissecting the role of the individual components of the immune system has led to better understand how they interact in concert to mediate the autoimmune response in young and elderly people and in those with autoimmune diseases.
RELENT research is designed to explore novel pathways to meet the urgent need for more individualised therapeutic strategies for chronic autoimmune and inflammatory disease. The results to date of the innovative research in RELENT have confirmed the hypotheses set out in the Work Programme and unlocked directions for novel treatment strategies. Moreover, they led to the discovery of novel, unexpected pathogenetic mechanisms. The pathways discovered will lead to measures for better disease monitoring and the development of biomarkers that, with the help of one of RELENT’s SME partner allowed translation into clinically applicable assays. Thus, the research of RELENT that will change our current understanding of autoimmunity and broaden our tools to investigate and monitor them.