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Background Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s diseases, is recognized as an autoimmune disorder characterized by chronic inflammation of the digestive tract. Long-term inflammation can lead to fibrosis, intestinal stenosis, and obstruction, and sometimes requires surgical intervention. It has been reported that Tumor Necrosis Factor-like Ligand 1A (TL1A) binds to its receptor DR3, amplifying immune responses and accelerating fibrosis associated with IBD. In addition, targeting TL1A can effectively inhibit the excessive immune activity of the body, delay disease progression, and improve the prognosis of patients.Methods TNBS solution was instilled into the colon lumen of B-hTL1A/hIL23A/hIL12B mice (female, 8 to 10 weeks old, n=10). On Day 0, the control group (Sham) received intrarectal injections of 50% ethanol. The treatment groups received 10 mpk anti-human TL1A antibody Tulisokibart, 10 mpk anti-human IL-23 p19 antibody Risankizumab, alone or in combination. Body weight and DAI score were recorded daily. On Day 5, mice were sacrificed, and colon length and weight were recorded. Colon tissue was later used for H&E staining and Masson’s trichrome staining. The blood and colon tissue were collected for cytokines detection.Results The severe weight loss and increased DAI scores in the Vehicle group confirmed the successful establishment of the TNBS-induced colitis model. The anti-human TL1A antibody Tulisokibart, anti-human IL-23 p19 antibody Risankizumab, alone or in combination, reduced the weight loss, DAI scores and inflammatory cytokines release (IL-1β, IL-6, IL-17A, IFN-γ, and TNF-α in serum and colon) in all the treatment groups. The histological analysis showed that the anti-human TL1A antibody Tulisokibart, anti-human IL-23 p19 antibody Risankizumab, alone or in combination, could reverse the inflammatory cell infiltration, crypt structure change and fibrosis in the colon tissue.Conclusions In this study, we successfully established the TNBS-induced colitis model in transgenic humanized mice. Treatment with anti-human TL1A antibody Tulisokibart, anti-human IL-23 p19 antibody Risankizumab, alone or in combination, can effectively alleviate the symptoms of TNBS-induced colitis in transgenic humanized mice. These results highlight the potential of targeting TL1A to become a ‘Best-in-Class’ therapy for IBD treatment.