Levamisole-Mediated Suppression of B-Cell Proliferation and Antibody Production Reveals Mechanistic Insights into Idiopathic Nephrotic Syndrome Therapy

Abstract Levamisole (LMS) is a small imidazole derivative with immunomodulatory properties. Despite its longstanding clinical use in Idiopathic Nephrotic Syndrome (INS), the mechanisms underlying its immune-regulating effects remain poorly defined. In this study, we investigated the in vitro effects of LMS treatment on human B-cells, and in patients included from the LEARNS (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome) clinical trial. In vitro experiments showed that LMS directly suppresses activation and proliferation in both T-cell dependent and T-cell independent stimulated B-cells, without inducing cytotoxicity. In agreement, transcriptomic profiling demonstrated downregulation of cell cycle-associated genes and genes involved in immunoglobulin synthesis, while genes involved in terminal B-cell differentiation were upregulated, including SLAMF7. Consistently, LMS treatment decreased immunoglobulin expression and secretion while simultaneously inducing the expression of factors associated with a more terminal B-cell phenotype (CD138/CD319). Flowcytometry analysis of blood samples from LMS-treated INS patients revealed reduced circulating B-cell counts. Collectively, these data suggest that LMS acts as a potent modulator of B-cell function that inhibits proliferation and immunoglobulin synthesis, providing mechanistic support for its therapeutic efficacy in INS management. Competing Interest Statement The authors have declared no competing interest.