Background/Purpose: Rodent models mimic some aspects of human lupus disease manifestations in various tissues, such as kidney, skin, joint, and CNS. NZB/NZW F1 and MRL/lpr models have been used extensively for gaining understanding of disease driving mechanism as well as pharmacological evaluation of new therapies.  However, the translatability of therapeutic results from rodent lupus models to human lupus patients is limited.  Here, we explored the feasibility of using a combination of clinically relevant methods, such as biochemistry analysis, terminal histology, and in vivo imaging modalities, to characterize and/or quantify specific inflammatory pathways/tissue damage and to evaluate treatment effect in MRL/lpr mice.

Methods: Female MRL/lpr mice were treated with cyclophosphamide (50 mg/kg i.p. qw) starting at 6-8 weeks of age.  Disease development was monitored by gross skin lesion scoring, conventional blood (anti-dsDNA and blood urea nitrogen) and urine (proteinuria) biochemistry, and terminal skin and kidney H&E histology analyses.  Disease phenotypes were also monitored longitudinally in vivo using multi-modality imaging. Changes in glomerular filtration rate (GFR) were tracked by contrast agent Omnipaque washout using micro-computed tomography (micro-CT). Myeloperoxidase-dependent reactive oxygen species (ROS) production by neutrophils/myeloid cells was quantified with luminol-bioluminescence imaging (luminol-BLI) to monitor skin and joint inflammation. Finally, changes in cerebral cortical thickness and ventricle size were measured by brain magnetic resonance imaging (MRI).  

Results: MRL/lpr mice treated with cyclophosphamide had no detectable production of anti-nuclear antibodies and exhibited with minimal skin and kidney disease phenotype. Neutrophil activation and ROS production in the skin and hind limbs visualized by luminol-BLI was detectable at 12 weeks of age and preceded gross skin lesion observation at 14 weeks of age. MicroCT detected a GFR decrease as early as 14 weeks of age in MRL/lpr mice, compared to the blood urea nitrogen level increase at 16 weeks of age. Skin and kidney imaging results correlated with the terminal tissue H&E histology evaluation.  Furthermore, MRI of the brain detected cerebral cortical thinning as early as 10 weeks of age in MRL/lpr mice.  Cyclophosphamide treatment resulted in reduced progression of the cerebral cortical thinning process in these mice. 

Conclusion: Here for the first time we have successfully demonstrated that evaluation of disease progression and treatment effect can be achieved by a combination of in vivo imaging, blood biochemistry, and terminal histological analysis in MRL/lpr model. The novel non-invasive imaging approach in MRL/lpr model captured disease progression and treatment effect efficiently. This comprehensive approach of combined in-life and terminal inflammation pathway/tissue damage evaluation in a pre-clinical lupus model provides a potential platform for translatable biomarkers of lupus diagnosis and treatment evaluation in drug discovery.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhance-translatability-using-multi-modality-disease-evaluation-approach-in-lupus-model/