Tofacitinib Citrate in a Murine Model of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) often manifests in lupus nephritis (LN), which injures glomeruli and leads to hypertension, and kidney failure. Despite a wide range of immunosuppressive therapies, many patients still show histologic signs of injury and others experience renal flares, which drive kidney disease progression. Tissue resident memory T cells (TRMs), which express adhesion molecules (CD103 and Cd49a) and who’s differentiation is controlled by cytokine signaling pathways like IL-15/JAK/STAT, are emerging mediators of chronic inflammatory and autoimmune diseases, representing a promising therapeutic target. Therefore, we hypothesize that kidney TRMs mediate kidney injury in SLE and that inhibiting JAK/STAT signaling will prevent their differentiation and improve kidney injury and function. To test this hypothesis female NZBWF1J mice (a genetic mouse model of SLE) were acquired at 4-weeks-old and aged to 28-weeks-old before being randomly assigned to receive either 20mg/kg tofacitinib citrate (SLE+Tofa) by oral gavage six days per week or 5% methylcellulose (SLE+Veh) for four weeks. Female NZW mice were used as controls. SLE+Tofa mice had significant weight loss between week 28 to 32 (48.2 ± 2.1 vs 40.3 ± 1.3 g, p=0.002), but SLE+Veh (p=0.093) and NZW (p=0.074) did not. Log-rank (Mantel-Cox) test indicated significant differences in time to albuminuria onset (Chi square 16.01, df = 2, p = 0.0003). Pairwise comparison of SLE+Tofa and SLE+Veh demonstrated SLE+Veh had a higher risk of albuminuria onset (HR = 11.85, 95% CI 1.53-91.79). Furthermore, at 32 weeks albuminuria levels were significantly higher in the SLE+Veh group compared to SLE+Tofa (3.6 ± 1.9 vs 1.0 ± 0 AU, p=0.0002) and Control groups (0 ± 0 AU, p0.999). In summary, tofacitinib citrate treated mice had improved GFRs and reductions in proteinuria and histological signs of injury. Reductions in kidney TRMs may explain the improvements in kidney function and injury, although reductions in total T cell populations and broader inhibition of JAK/STAT signaling, which is a common inflammatory pathway in all cell types, may also be responsible. Additionally, increasing sample sizes will be necessary to determine the true relationship between JAK/STAT inhibition, TRM depletion, and improvements in kidney parameters in SLE. In conclusion, JAK/STAT inhibition may be a viable therapeutic option for the treatment of LN in SLE, and its benefits may be exerted through reductions in key inflammatory TRM populations. UAB Blalock PhD Career Development Award This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.