Evaluation of Mycophenolate Mofetil and Galantamine Combination Therapy on Immunologic and Kidney Outcomes in a Murine Model of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease driven by systemic inflammation that promotes end-organ injury, including lupus nephritis and cardiovascular complications. Mycophenolate mofetil (MMF) is a foundational component of standard-of-care therapy for lupus nephritis, used alongside corticosteroids and often complemented by antimalarials or biologics. However, despite multi-drug regimens, many patients fail to achieve durable remission, and MMF is further limited by immunosuppression-related infection risk, tolerability concerns, and cost barriers that restrict long-term adherence. We have shown previously that galantamine (GAL), an FDA-approved, widely accessible acetylcholinesterase inhibitor that enhances cholinergic anti-inflammatory signaling, reduces kidney inflammation and disease severity in murine SLE. Given the need for adjunctive therapies that can strengthen efficacy without adding substantial toxicity, we hypothesized that combining galantamine with a deliberately reduced MMF dose would enhance immunologic and kidney outcomes in lupus-prone mice. Female NZBWF1 mice, an established model of SLE, received low-dose MMF (30 mg/kg/day, IP), GAL (4 mg/kg/day, SC), or combination therapy (MMF+GAL), for two weeks starting at 33 weeks of age. Retro-orbital blood, splenic tissue and urine were collected at 35 weeks. Plasma anti-dsDNA autoantibodies, a hallmark of SLE, were quantified by ELISA. Splenic tissue was analyzed by flow cytometry to determine the distribution of immune cell populations, including T and B cells. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1, markers of renal injury, were quantified by ELISA. Plasma anti-dsDNA autoantibodies were significantly lower in SLE mice receiving combination therapy (338.5 ± 69.9 kU/mL) compared to MMF monotherapy (639.2 ± 106.2; p = 0.0224). In contrast, the proportion (% cells) of CD3+ T cells and CD19+ B cells did not differ between SLE mice treated with MMF monotherapy and combination therapy (31.80 ± 3.77 vs. 30.18 ± 0.47; p = 0.9920 and 54.88 ± 3.87 vs. 54.00 ± 0.27; p = 0.9990, respectively). Similarly, combination therapy did not significantly alter urinary NGAL (9.853e6 ± 6.25e6 pg/mL) or KIM-1 levels (17,589 ± 5,396 pg/mL) in SLE mice compared with MMF monotherapy (3.33e6 ± 2.26e6; p = 0.6955 and 15,356 ± 3138; p = 0.9897, respectively). Together, our work revealed that adjunctive galantamine augments select beneficial immunologic effects of MMF, providing preliminary evidence that combination therapy can be effective in mitigating complications associated with SLE. Given its established safety profile, FDA approval, and accessibility, galantamine represents a feasible and potentially cost-effective adjunctive strategy meriting further investigation in SLE. Studies funded by Department of Defense (LR210096), NIH R01HL153703, and UTSW Startup Funds for KWM 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.