A Novel Human Interleukin-23A Overexpressing Mouse Model of Systemic Lupus Erythematosus.

Abstract

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. 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. 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. 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.