Role of Trained Immunity in the pathogenesis and treatment of Still’s disease

In order to test the hypotheses the following aims are proposed:

• AIM 1: to determine epigenetic and immunometabolic features of TI in SD monocytes.
• AIM 2: to determine the therapeutic potential of inhibiting TI for the treatment of SD.

• Month 12: identification of functional and epigenetic features of TI in SD monocytes.
• Month 24: identification of immunometabolic features of TI in SD monocytes.
• Month 30: evaluation of TI as a predictor of clinical outcomes in SD.
• Month 36: Identification of strategies effectively inhibiting TI for the treatment of SD.

• Ferrero E, Villa A, Stefanoni D, Nemkov T, D'Alessandro A, Tengesdal I, Belloni D, Molteni R, Vergani B, De Luca G, Grassini G, Cangi MG, Dagna L, Doglioni C, Cavalli G, Ferrarini M. Immunometabolic activation of macrophages leads to cytokine production in the pathogenesis of KRAS-mutated histiocytosis.. Rheumatology (Oxford). 2022 Apr 11;61(4):e93-e96. doi: 10.1093/rheumatology/keab869.PMID: 34919661
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• Molteni R, Biavasco R, Stefanoni D, Nemkov T, Domínguez-Andrés J, Arts RJ, Merelli I, Mazza D, Zambrano S, Panigada M, Cantoni E, Tengesdal IW, Maksud P, Piras F, Cesana D, Cassina L, Distefano G, Loffreda A, Gnani D, De Luca G, Tomelleri A, Campochiaro C, Joosten LAB, Dinarello CA, Kajaste-Rudnitski A, Haroche J, Cardaci S, Cenci S, Dagna L, Doglioni C, Ferrarini M, Ferrero E, Boletta A, D'Alessandro A, Montini E, Netea MG, Cavalli G. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease. Blood. 2021 Oct 28;138(17):1554-1569. doi: 10.1182/blood.2020009594.PMID: 34077954
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• Cavalli G, Tengesdal IW, Gresnigt M, Nemkov T, Arts RJW, Domínguez-Andrés J, Molteni R, Stefanoni D, Cantoni E, Cassina L, Giugliano S, Schraa K, Mills TS, Pietras EM, Eisenmensser EZ, Dagna L, Boletta A, D'Alessandro A, Joosten LAB, Netea MG, Dinarello CA. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity. Cell Reports. 2021 Apr 6;35(1):108955. doi: 10.1016/j.celrep.2021.108955.PMID: 33826894
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This study is important to many patients with AOSD and SJIA, and many already volunteered to donate samples. In collaboration with AMRI (a non-profit patient organisation with investment in SD) there is a strong engagement of patients in the research process.

Regular updates on research findings, instructions on research strategies based on patients’ insight, and development for shared initiatives for effective dissemination of findings to societal stakeholders will be provided.