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, p< 0.0001). GFRs at 32 weeks of age were significantly decreased in the SLE+Veh group compared to SLE+Tofa (524 ± 165 vs 971 ± 49 mL/min/100g, p=0.005) and Control groups (805 ± 42 mL/min/100g, p=0.047). Examination of H&E histological sections revealed severe tubular dilation and atrophy, leukocytic infiltrates, and glomerular injury (collapse and mesangial expansion) in SLE+Veh specimens that had early proteinuria (300mg/dL+ by 30 weeks), while SLE+Veh specimens without proteinuria or late onset proteinuria showed few signs of injury. SLE+Tofa and control specimens showed no histological signs of injury. There was a trend towards increased CD49a+ CD8 TRMs in SLE+Veh compared to controls (2842 ± 1782 vs 414 ± 169 cells/kidney, p=0.055), while the SLE+Tofa group was not increased compared to controls (29 ± 8 cells/kidney, p=0.908) and was decreased compared to SLE+Veh (p=0.0496). There was a significant increase in CD103+ CD8 TRMs in the SLE+Veh group compared to controls (1567 ± 983 vs 260 ± 40 cells/kidney, p=0.0456) and while the SLE+Tofa group trended towards a decreased compared to SLE+Veh (p=0.835), the SLE+Tofa group was not increased compared to controls (256 ± 107 cells/kidney, p >0.999). 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.