A NOVEL HUMAN IL23A-DRIVEN MOUSE MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS
Bibliographic record
Abstract
PV009 / #339 Poster Topic: AS02 - Animal Models Background/Purpose Interleukin 23, a member of the IL12 cytokine family, has been implicated in the reprogramming of immune cells by inducing and maintaining their proinflammatory state. It acts as a heterodimer composed of 2 subunits IL23A and IL12B and it has been shown to play a lead role in pathogenic mechanisms involved in the development of immune-mediated inflammatory diseases like psoriasis, inflammatory bowel disease etc. To further explore the contribution of IL23A in disease pathogenesis we generated a transgenic mouse expressing deregulated levels of the human IL23A subunit (TghIL23A) and characterized the phenotypes developed. Methods To achieve deregulated levels of expression of the human IL23A subunit, we designed the TghIL23A transgene containing the complete intron-exon sequence of human IL23A gene under the human IL23A promoter, with its 3’UTR replaced with the human-beta-globin in order to abolish all posttranscriptional regulation. Signs of overt pathology included skin lesions which were assessed clinically and all affected organs, including skin, liver, lungs, spleen and lymph nodes were examined histopathologically. Biochemical and hematological analyses were used for the evaluation of blood and urine samples, while biomarkers of pathology including cytokines and antinuclear antibodies, were assessed at different ages by ELISA and molecular analyses. Both overt pathology signs and biological fluids analyses were assessed in crosses of TghIL23A to IL12BKO and Rag1KO mice. The response of the TghIL23A mice to human therapeutics was assessed by treating them twice weekly with guselkumab. Results The human IL23A subunit in the transgenic mice that we generated could form active IL23 entities by forming heterodimers with its mouse partner and resulted in the development of clinical phenotypes that involved chronic inflammatory lesions in the skin, kidney and lungs as well as enlargement of the spleen and local lymph nodes. Signs of the developing pathology also included the development of proteinuria, circulating anti-dsDNA antibodies, increased levels of circulating IgGs that were gradually found deposited in kidney glomeruli and skin. The formation of human-mouse heterodimers was supported by the abolishment of the phenotypes upon crossing the TghIL23A to IL12BKO, while the autoimmune nature of the developing pathologies was supported by the abolishment of the pathologies upon crossing to Rag1KO mice that lack a functional immune system. The above-described pathological features exhibit significant similarities to those observed in human SLE patients supporting that the transgenic mouse that we developed can serve as novel mouse model of lupus erythematosus with cutaneous implications. Interestingly, our preliminary evidence indicates that equally to IL23A, mice expressing the human IL12B subunit show similar signs of lupus. 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 integrate several characteristics of the human disease complexity and chronicity making it attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and for the evaluation of human therapeutics targeting the human IL23 pathway.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".