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Background & Aims: Inflammatory bowel diseases are multifactorial diseases commonly treated with either immunomodulatory drugs or anti–tumor necrosis factor (TNF). Currently, failure to respond to anti-TNF therapy (assessed no earlier than 8–12 weeks after starting treatment) occurs in 20%–40% of patients enrolled in clinical trials and in 10%–20% in clinical practice. Murine models of inflammatory bowel disease provide important tools to better understand disease mechanism(s). In this context and among the numerous models available, Winnie–TNF–knockout (KO) mice recently were reported to show characteristics of ulcerative colitis (UC) that are independent of TNF, and with increased interleukin (IL)1β production. Methods: Herein, the efficacy of recombinant IL1-receptor antagonist (anakinra) administration was evaluated in Winnie-TNF-KO mice, used as a UC model of primary anti-TNF nonresponders. Results: We analyzed gut mucosal biopsy specimens and circulating cytokine profiles of a cohort of 30 UC patients; approximately 75% of primary nonresponders were characterized by abundant IL1β in both the serum and local intestinal tissues. In Winnie-TNF-KO mice, administration of anakinra efficiently reduced the histologic score of the distal colon, which represents the most common site of inflammation in Winnie mice. Furthermore, among lamina propria and mesenteric lymph node–derived T cells, interferon γ–expressing CD8+ T cells were reduced significantly after anakinra administration. Conclusions: Our study provides new insight and alternative approaches to treat UC patients, and points to anti-IL1 strategies (ie, anakinra) that may be a more effective therapeutic option for primary nonresponders to anti-TNF therapy.