This newest addition in our collection of humanized mouse disease models integrates characteristics of the human Systemic Lupus Erythematosus complexity and develops a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin and milder pathologies in the kidneys and lungs.

This novel model of lupus can prove to be an invaluable translational tool for studying the aetiopathogenic role of the IL23 cytokine in SLE and for use as a preclinical tool to assess the efficacy of novel  lupus  therapeutics.

Published in Arthritis Rheumatol. 2024 Feb 15. doi: 10.1002/art.42830.

Christodoulou-Vafeiadou E, Geka C, Iliopoulou L, Ntari L,  Denis MC, Karagianni N, Kollias G

Objective: Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases like psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model (TghIL23A) overexpressing human IL23A, providing a valuable tool for investigating the pathogenic role of hIL23A and evaluating the efficacy of anti-human-IL23A therapeutics.

Methods: TghIL23A mice were generated via microinjection of CBAxC57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5′-regulatory sequences and the 3’UTR of human beta-globin. The TghIL23A pathology was assessed through hematological and biochemical analyses, cytokine and anti-nuclear antibody detection, histopathological examination of skin and renal tissues. The response to the anti-hIL23A therapeutic agent guselkumab, was evaluated in groups of 8 mixed-sex mice receiving subcutaneous treatment twice weekly for 10 weeks, using clinical, biomarker and histopathological readouts.

Results: TghIL23A mice exhibited interactions between hIL23A and mouse IL23/IL12p40, and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin, and milder phenotypes in the kidneys and lungs. The TghIL23A pathological features exhibited significant similarities to those observed in human SLE patients and they were reversed following guselkumab treatment.

Conclusions: We have generated and characterized a novel genetic mouse model of SLE, providing proof-of-concept for the etiopathogenic role of hIL-23A. This new model has a normal lifespan and integrates several characteristics of the human disease’s complexity and chronicity making it an attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and assessing the efficacy of anti-hIL23A or modeled disease-related therapeutics.

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With a new publication in Arthritis Research and Therapy, entitled “Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis”, Biomedcode in collaboration with George Kollias Lab at BSRC Al. Fleming, introduce the TgA86 transmembrane TNF transgenic mouse as a novel model of human spondyloarthritis (SpA).

The authors show that the TgA86 mouse model develops spontaneously peripheral arthritis and axial pathologies that closely reproduce key pathogenic features of human SpA, including distinct stages of inflammation and ectopic new bone formation. This is a chronic and complex disease model that similar to human patients also develops extraarticular comorbidities such as heart valve pathology and systemic bone loss. As with human patients in the clinic, all the pathologies of the TgA86 mouse model are reversed following early treatment with anti-hTNF therapeutics.

This novel model of SpA that captures not only specific features, but also the complexity of human disease, can prove to be an invaluable translational tool in the study of SpA pathogenesis as well as in the evaluation of human therapeutics.

Published in Arthritis Research and Therapy 2020 Oct 6;22(1):232. doi: 10.1186/s13075-020-02327-4.

Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis

Christodoulou-Vafeiadou E, Geka C, Ntari L, Kranidioti K, Argyropoulou E, Meier F, Armaka M, Mourouzis I, Pantos C, Rouchota M, Loudos G, Denis MC, Karagianni N, Kollias G

Background: The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model.

Methods: TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis.

Results: TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice.

Conclusions: The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

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Scientists of Biomedcode present in PLOS Computational Biology a new computational framework revealing key differences between four rheumatoid arthritis medications and their impact on biological pathways in mice.

Published in PLoS Computational Biology 2019 May 9;15(5):e1006933. doi: 10.1371/journal.pcbi.1006933

Anti-TNF agents have been in the first line of treatment of various inflammatory diseases such as Rheumatoid Arthritis and Crohn’s Disease, with a number of different biologics being currently in use. A detailed analysis of their effect at transcriptome level has nevertheless been lacking. We herein present a concise analysis of an extended transcriptomics profiling of four different anti-TNF biologics upon treatment of the established hTNFTg (Tg197) mouse model of spontaneous inflammatory polyarthritis. We implement a series of computational analyses that include clustering of differentially expressed genes, functional analysis and random forest classification. Taking advantage of our detailed sample structure, we devise metrics of treatment efficiency that take into account changes in gene expression compared to both the healthy and the diseased state. Our results suggest considerable variability in the capacity of different biologics to modulate gene expression that can be attributed to treatment-specific functional pathways and differential preferences to restore over- or under-expressed genes. Early intervention appears to manage inflammation in a more efficient way but is accompanied by increased effects on a number of genes that are seemingly unrelated to the disease. Administration at an early stage is also lacking in capacity to restore healthy expression levels of under-expressed genes. We record quantifiable differences among anti-TNF biologics in their efficiency to modulate over-expressed genes related to immune and inflammatory pathways. More importantly, we find a subset of the tested substances to have quantitative advantages in addressing deregulation of under-expressed genes involved in pathways related to known RA comorbidities. Our study shows the potential of transcriptomic analyses to identify comprehensive and distinct treatment-specific gene signatures combining disease-related and unrelated genes and proposes a generalized framework for the assessment of drug efficacy, the search of biosimilars and the evaluation of the efficacy of TNF small molecule inhibitors.

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Patients with rheumatoid arthritis and spondyloarthritis show higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymal synovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities.

Published in Annals of Rheumatic Diseases 2018 Jun;77(6):926-934. doi: 10.1136/annrheumdis-2017-212597.

Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis

Ntari L, Sakkou M, Chouvardas P, Mourouzis I, Prados A, Denis MC, Karagianni N, Pantos C, Kollias G.

Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative ColVI-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype ex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities.

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