Spontaneous MRL/LPR Model of SLE
Systemic Lupus Erythematosus (SLE) is a chronic, inflammatory, systemic autoimmune disease affecting multiple organ systems. Common characteristics of SLE include kidney disease, skin eruptions, joint pain, pulmonary, and neuropsychiatric complications. Vium offers a commonly used murine model of lupus (MRL/MpJ-Faslpr (MRL/lpr)) against which to validate the efficacy of potential therapeutic compounds (1). The MRL/lpr mice spontaneously develop disease that closely mimics human SLE pathologies including nuclear autoantibody production, enlargement of lymph nodes, skin lesions, hypergammaglobulinemia (increased IgG levels), proteinuria, and kidney failure (2-4). In this model, various immune cell populations (5-7,) including B and T cells, contribute to the pathogenesis of the disease.
- Breathing Rate
Optional Conventional Measures
- Proteinuria score (1/week)
- Anti-dsDNA titration (1/month)
- Organ histopathology (study end)
Six-week old male C57BL/6J and C3H/HeJ mice were acclimated to the Vium Digital Vivarium™ for a total of one week prior to commencing the study. Animals were singly housed three days prior to study start. Unrestrained animals were placed in a whole-body plethysmograph (EMKA technologies), and their breathing rate was simultaneously collected via plethysmograph and the Vium Breathing Rate algorithm.
Most patients with SLE show signs of lung involvement, including dyspnea. MRL/lpr mice display elevated breathing rates as disease progresses (see Fig. 1B). Frequent assessment of breathing rates allows researchers to compare breathing rates across the course of the disease as well as focus on changes before and after therapeutic interventions.
Animals are monitored in Vium Smart Housing™ from arrival at the age of 6 weeks. Conventional weekly measures of proteinuria and body weights can be collected to follow disease onset and progression. Monitoring continues until the end of study (generally 13-15 weeks later) when necropsy is performed.
Figure 1: Sample study data demonstrating a significant reduction in night time motion (A) and a significant increase in breathing rate (B) that occurs as disease progresses. Mice were 28 days old on study day 0. Arrow represents disease onset as measured by proteinuria scores. N = 10-30/group.
Organ weights (spleen, lymph nodes, kidneys) are collected and histopathology (spleen, kidney) performed to score the severity of the disease. Blood collection may also be performed at regular intervals and at end of study to assess level of biomarkers such as anti-dsDNA. Disease onset occurs generally around the age of 12 weeks. Median survival is 17 and 22 weeks of age respectively for MRL/lpr female and male mice.
Prior to treatment, mice are randomized into groups ensuring both body weight, motion, and proteinuria scores are similar between all groups.
For prophylactic studies, test compounds are administered (SC, PO, IP or IV) beginning between 8-10 weeks of age, prior to disease onset. For therapeutic studies, test compounds are administered (SC, PO, IP or IV) after disease onset, which is defined by proteinuria score equal or greater than 2 (>100 mg/dL).
POSITIVE CONTROL THERAPEUTICS
- 24/7 motion activity (nightly, daily and circadian motion)
- Breathing rate (daily and weekly averages)
- Proteinuria scores
- Blood biomarkers: anti-dsDNA
- Tissue histology (kidneys, lungs and spleen)
- Lymphoadenopathy and skin lesions assessment
- Spleen and lymph node weights
Plots and statistical analysis for all measures are available on the Vium Analytics Studio.
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