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 Ca 2؉ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca 2؉ 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 Ca 2؉ 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 Ca 2؉ levels and T cell activation-induced rapid Ca 2؉ 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 Ca 2؉ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown origin. It involves multiple organs including the joints, skin, kidneys, and central nervous system and is characterized by a waxing and waning course. We have previously discovered that mitochondrial dysfunction, characterized by elevation of the mitochondrial transmembrane potential and depletion of ATP, plays key roles in aberrant apoptosis and predisposition to necrosis, and likely significantly contributes to the inflammatory process in SLE (1). Recent observations have indicated that mitochondrial dysfunction is associated with enhanced Ca 2ϩ fluxing in T lymphocytes from patients with SLE (2,3), providing potential new therapeutic targets (4-6).Rapamycin (sirolimus) is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopius. The intracellular rapamycin receptor is a small, 12-kd FK-506 binding protein (FKBP12). The rapamycin-FKBP12 complex interacts with mammalian target of rapamycin (mTOR), a protein kinase that controls T cell activation (7), by influencing gene transcription and multiple metabolic pathways, including Ca 2ϩ fluxing (8) and maintenance of the mitochondri...

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

“…RAPA significantly reduced or prevented many pathologic features of lupus normally seen in the MRL/lpr mouse [67]. RAPA treatment of patients with SLE normalized cytosolic and mitochondrial Ca 2+ levels and T cell activation-induced rapid Ca 2+ fluxing, without influencing MHP [68], indicating that increased Ca 2+ fluxing is downstream or independent of MHP in the pathogenesis of T-cell dysfunction in SLE. Interestingly, the mammalian target of rapamycin (mTOR) may be activated by enhanced production of NO [69].…”

A 50‐Year‐Old Woman With Cowden Syndrome and Joint Pains

“…A small study of SLE patients treated with rapamycin showed improvement in disease activity and steroid dose reduction (22). Another pathway for activation of mTOR in lupus T cells is from depletion of glutathione, which regulates the elevation of mitochondrial transmembrane potential or mitochondrial hyperpolarization (23).…”

m-TOR Inhibitors in the Current Practice

“…Rapamycin in theory would suppress geroconversion downstream of progerin. Furthermore, rapamycin prevents atherosclerosis in animal models of accelerated atherosclerosis and accelerated atherosclerosis is one of the main symptoms of progeria leading to death [73].…”