George Kollias

Objective Interleukin‐23 (IL‐23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases such as psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model overexpressing human IL‐23A (TghIL‐23A), providing a valuable tool for investigating the pathogenic role of human IL‐23A and evaluating the efficacy of anti–human IL‐23A therapeutics. Methods TghIL‐23A mice were generated via microinjection of CBA × C57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5′‐regulatory sequences and the 3′ untranslated region of human β‐globin. The TghIL‐23A pathology was assessed through hematologic and biochemic analyses, cytokine and antinuclear antibody detection, and histopathologic examination of skin and renal tissues. The response to the anti–human IL‐23A therapeutic agent guselkumab was evaluated in groups of eight mixed‐sex mice receiving subcutaneous treatment twice weekly for 10 weeks using clinical, biomarker, and histopathologic readouts. Results TghIL‐23A mice exhibited interactions between human IL‐23A and mouse IL‐23/IL‐12p40 and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti–double‐stranded DNA antibodies, severe inflammatory lesions in the skin, and milder phenotypes in the kidneys and lungs. The TghIL‐23A pathologic features exhibited significant similarities to those observed in human patients with SLE, and they were reversed following guselkumab treatment. Conclusion We have generated and characterized a novel genetic mouse model of SLE, providing proof‐of‐concept for the etiopathogenic role of human IL‐23A. This new model has a normal life span and integrates several characteristics of the human disease's complexity and chronicity, making it an attractive preclinical tool for studying IL‐23–dependent pathogenic mechanisms and assessing the efficacy of anti–human IL‐23A or modeled disease‐related therapeutics. image