Rapamycin reduces disease activity and normalizes T cell activation–induced calcium fluxing in patients with systemic lupus erythematosus

Abstract

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca²⁺ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca²⁺ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus‐prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE. Methods Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca²⁺ fluxing were assessed by flow cytometry. Results In patients treated with rapamycin, the BILAG score was reduced by a mean ± SEM of 1.93 ± 0.9 (P = 0.0218), the SLEDAI by 5.3 ± 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 ± 6.7 mg/day (P = 0.0062) compared with pre–rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca²⁺ levels and T cell activation–induced rapid Ca²⁺ fluxing were normalized in rapamycin‐treated patients. Conclusion Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca²⁺ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.